|
1
|
Atta AM, Rihan N, Abdelwaly AM, Nafie MS, Elgawish MS, Moustafa SM, Helal MA, Darwish KM. Development, biological evaluation, and molecular modelling of novel isocytosine and guanidine derivatives as BACE1 inhibitors using a fragment growing strategy. RSC Med Chem 2025:d4md00698d. [PMID: 40093519 PMCID: PMC11904611 DOI: 10.1039/d4md00698d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 01/28/2025] [Indexed: 03/19/2025] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising in vitro inhibitory activity against BACE1 down to sub-micromolar IC50. Docking simulation studies were performed to understand the mode of binding of the prepared compounds. We demonstrated that compounds with superior activities, such as 16b and 16g, are able to provide the best balance between the steric shape and position of the polar substituent for achieving preferential anchoring into the S1, S3, S1', and S2' sub-pockets. Further, in vivo characterization of selected drug-like candidates of the benzimidazole series AMK-IV, namely 16a and 16k, demonstrated their ability to reduce oxidation stress and their safety within brain and liver tissues.
Collapse
Affiliation(s)
- Asmaa M Atta
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC) Badr City Cairo (P.O. 11829) Egypt
| | - Nouran Rihan
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology Giza (P.O. 12587) Egypt
| | - Ahmad M Abdelwaly
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology Giza (P.O. 12587) Egypt
- Institute for Computational Molecular Science, and, Department of Chemistry, Temple University Philadelphia Pennsylvania (P.O. 19122) USA
| | - Mohamed S Nafie
- Department of Chemistry, College of Sciences, University of Sharjah Sharjah (P.O. 27272) United Arab Emirates
- Chemistry Department, Faculty of Science, Suez Canal University Ismailia (P.O. 41522) Egypt
| | - Mohamed S Elgawish
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia (P.O. 41522) Egypt
- Center for Molecular Spectroscopy and Dynamics, Institute of Basic Science, Korea University Seoul (P.O. 02841) Republic of South Korea
| | - Samia M Moustafa
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia (P.O. 41522) Egypt
| | - Mohamed A Helal
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology Giza (P.O. 12587) Egypt
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia (P.O. 41522) Egypt
| | - Khaled M Darwish
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University Ismailia (P.O. 41522) Egypt
- Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University New Galala (P.O. 43713) Egypt
| |
Collapse
|
|
2
|
Malikova I, Worth A, Aliyeva D, Khassenova M, Kriajevska MV, Tulchinsky E. Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us? Cell Death Dis 2025; 16:155. [PMID: 40044635 PMCID: PMC11883011 DOI: 10.1038/s41419-025-07480-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/09/2025]
Abstract
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
Collapse
Affiliation(s)
- Ilona Malikova
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | - Anastassiya Worth
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | - Diana Aliyeva
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | - Madina Khassenova
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
| | - Marina V Kriajevska
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - Eugene Tulchinsky
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan.
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
| |
Collapse
|
|
3
|
Choi E, Duan C, Bai XC. Regulation and function of insulin and insulin-like growth factor receptor signalling. Nat Rev Mol Cell Biol 2025:10.1038/s41580-025-00826-3. [PMID: 39930003 DOI: 10.1038/s41580-025-00826-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2025] [Indexed: 03/24/2025]
Abstract
Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin-IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin-IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin-IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin-IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin-IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand-receptor interactions and functions of insulin-IGF receptor signalling in diseases.
Collapse
Affiliation(s)
- Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Cunming Duan
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Xiao-Chen Bai
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
4
|
Zhan Y, Chen Z, Zheng S, Dai L, Zhang W, Dai Y, Gao F, Shen Y, Zhang W. Elevated BACE1 and IFNγ+ T Cells in Patients with Cognitive Impairment and the 5xFAD Mouse Model. ACS Chem Neurosci 2025; 16:384-392. [PMID: 39810314 PMCID: PMC11804866 DOI: 10.1021/acschemneuro.4c00565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
The dysregulation of T cell differentiation was associated with cognitive impairment. Recently, the peripheric β-secretase (BACE1) has been suggested as a regulator of T cell differentiation, which was increased in both cognitive impairment (CI) and type 2 diabetes mellitus (T2DM) in CI patients. However, the relationship between T cell dysfunction and CI remains unclear. To address this question, we measured T cell subtypes and BACE1 enzyme activity in a clinical cohort and 5xFAD mice. We found that both IFNγ+ Th1 and Tc1 cells were increased in the CI and T2DM-CI groups, which were associated with worsening cognitive function. The elevated IFNγ + Th1 and Tc1 cells were also observed in 8-month-old 5xFAD mice. The elevated BACE1-mediated INSR cleavage was associated with increased IFNγ + Th1 and Tc1 cells. These findings demonstrate the potential role of elevated BACE1 in IFNγ+ T cells and CI.
Collapse
Affiliation(s)
- Yaxi Zhan
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Zuolong Chen
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Shuxin Zheng
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Linbin Dai
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Wei Zhang
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
| | - Yumeng Dai
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
| | - Feng Gao
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Yong Shen
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
- Neurodegenerative
Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
- Anhui Province
Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Huangshan Road 373, Hefei 230026, Anhui, China
| | - Weiwei Zhang
- Department
of International Medical, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, Lujiang Road 373, Hefei 230001, Anhui, China
| |
Collapse
|
|
5
|
Tosat-Bitrián C, Bueso de Barrio JA, Stewart MH, Susumu K, Medintz IL, Díaz SA, Palomo V. Membrane-Targeted Quantum Dot-Based BACE1 Activity Sensors for In Vitro and In Cellulo Assays. ACS APPLIED MATERIALS & INTERFACES 2024; 16:63186-63194. [PMID: 39515812 PMCID: PMC11583121 DOI: 10.1021/acsami.4c12560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/05/2024] [Accepted: 09/06/2024] [Indexed: 11/16/2024]
Abstract
The need for the development of specific and robust methodologies to elucidate the intricate pathological mechanisms of neurodegenerative diseases and discover effective treatments for prevention and remediation is evident. Alzheimer's disease, in particular, has become more prevalent as the global population has aged. β-Secretase, the β-site amyloid precursor protein cleaving enzyme (BACE1), is the protease that produces the β-amyloid peptide, which is considered one of the driving factors of Alzheimer's disease and an important target for treatment development. However, an understanding of its activity, modulation, and regulation is far from complete. This is in large part due to the complex nature of following its activity. Beyond the common requirements for all biosensors (ease of preparation and use), BACE1 probes also demand both stability at acidic pH and membrane localization. To overcome these hurdles, we exploit the modular self-assembly provided by fluorescent quantum dot (QD) sensors. As compared to other fluorophores, QDs provide enhanced fluorescence brightness and photostability, and their large surface area enables functionalization with peptide substrates together with targeting elements that localize the sensor to the areas of maximal BACE1 activity, all achieved through His-tag self-assembly. In vitro, the sensor demonstrated stability under acidic conditions, and using high-throughput plate reader assays, we determined BACE1 activity in-line with literature values and enabled the obtainment of the inhibitor constant of verubecestat, a small molecule inhibitor. The sensor was also transitioned to cellular experiments, where it demonstrated sensitivity to BACE1 activity and its modulation upon inhibitor treatment in a neuroblastoma cell line.
Collapse
Affiliation(s)
- Carlota Tosat-Bitrián
- Centro
de Investigaciones Biológicas “Margarita Salas”-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
- Centro
de Investigación Biomédica en Red en Enfermedades Neurodegenerativas,
(CIBERNED), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | | | - Michael H. Stewart
- Optical
Sciences Division, Code 5600, U.S. Naval
Research Laboratory, Washington, DC 20375, United States
| | - Kimihiro Susumu
- Optical
Sciences Division, Code 5600, U.S. Naval
Research Laboratory, Washington, DC 20375, United States
| | - Igor L. Medintz
- Center
for Bio/Molecular Science and Engineering, Code 6900, U.S. Naval Research Laboratory, Washington, DC 20375, United States
| | - Sebastián A. Díaz
- Center
for Bio/Molecular Science and Engineering, Code 6900, U.S. Naval Research Laboratory, Washington, DC 20375, United States
| | - Valle Palomo
- Centro
de Investigación Biomédica en Red en Enfermedades Neurodegenerativas,
(CIBERNED), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain
- Instituto
Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), C/Faraday 9, 28049 Madrid, Spain
- Unidad Asociada
al Centro Nacional de Biotecnología (CSIC), Darwin 3, 28049 Madrid, Spain
| |
Collapse
|
|
6
|
Wasson CW, De Lorenzis E, Clavane EM, Ross RL, Walker KA, Caballero-Ruiz B, Antinozzi C, Wells R, Migneco G, Brown JMY, Turvey SJ, Simmons KJ, Riobo-Del Galdo NA, Di Luigi L, McKimmie CS, Del Galdo F, Meakin PJ. The β-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch Signaling Axis. J Invest Dermatol 2024; 144:2197-2210.e4. [PMID: 38570030 DOI: 10.1016/j.jid.2024.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 04/05/2024]
Abstract
BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on β-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher β-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression.
Collapse
Affiliation(s)
- Christopher W Wasson
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Enrico De Lorenzis
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom; Division of Rheumatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Eva M Clavane
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Rebecca L Ross
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Kieran A Walker
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Begoña Caballero-Ruiz
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Cristina Antinozzi
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
| | - Rebecca Wells
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Gemma Migneco
- Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Jane M Y Brown
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Samuel J Turvey
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Katie J Simmons
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Natalia A Riobo-Del Galdo
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom; Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Luigi Di Luigi
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
| | - Clive S McKimmie
- Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
| | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom; Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, United Kingdom.
| | - Paul J Meakin
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom.
| |
Collapse
|
|
7
|
Fluca AL, Pani B, Janjusevic M, Zwas DR, Abraham Y, Calligaris M, Beltrami AP, Campos Corgosinho F, Marketou M, D'Errico S, Sinagra G, Aleksova A. Unraveling the relationship among insulin resistance, IGF-1, and amyloid-beta 1-40: Is the definition of type 3 diabetes applicable in the cardiovascular field? Life Sci 2024; 352:122911. [PMID: 39002609 DOI: 10.1016/j.lfs.2024.122911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/19/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
The concept of "type 3 diabetes" has emerged to define alterations in glucose metabolism that predispose individuals to the development of Alzheimer's disease (AD). Novel evidence suggests that changes in the insulin/insulin-like growth factor 1 (IGF-1)/growth hormone (GH) axis, which are characteristic of Diabetes Mellitus, are one of the major factors contributing to excessive amyloid-beta (Aβ) production and neurodegenerative processes in AD. Moreover, molecular findings suggest that insulin resistance and dysregulated IGF-1 signaling promote atherosclerosis via endothelial dysfunction and a pro-inflammatory state. As the pathophysiological role of Aβ1-40 in patients with cardiovascular disease has attracted attention due to its involvement in plaque formation and destabilization, it is of great interest to explore whether a paradigm similar to that in AD exists in the cardiovascular field. Therefore, this review aims to elucidate the intricate interplay between insulin resistance, IGF-1, and Aβ1-40 in the cardiovascular system and assess the applicability of the type 3 diabetes concept. Understanding these relationships may offer novel therapeutic targets and diagnostic strategies to mitigate cardiovascular risk in patients with insulin resistance and dysregulated IGF-1 signaling.
Collapse
Affiliation(s)
- Alessandra Lucia Fluca
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Beatrice Pani
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Milijana Janjusevic
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Donna R Zwas
- Linda Joy Pollin Cardiovascular Wellness Center for Women, Heart Institute, Hadassah University Medical Center, Jerusalem, Israel
| | - Yosefa Abraham
- Department of Human Nutrition and Metabolism, School of Public Health Medical Faculty Jerusalem, Jerusalem, Israel
| | - Matteo Calligaris
- Department of Medicine (DMED), Università degli Studi di Udine, Udine, Italy
| | - Antonio Paolo Beltrami
- Department of Medicine (DMED), Università degli Studi di Udine, Udine, Italy; Azienda Sanitaria Universitaria Friuli Centrale, Istituto di Patologia Clinica, Udine, Italy
| | | | - Maria Marketou
- Heraklion University General Hospital, University of Crete, School of Medicine, Cardiology Department, Crete, Greece
| | - Stefano D'Errico
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Gianfranco Sinagra
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Aneta Aleksova
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy.
| |
Collapse
|
|
8
|
Katusic ZS, d’Uscio LV, He T. Cerebrovascular Endothelial Dysfunction: Role of BACE1. Arterioscler Thromb Vasc Biol 2024; 44:1737-1747. [PMID: 38868939 PMCID: PMC11269044 DOI: 10.1161/atvbaha.124.320798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Abstract
Dysfunctional endothelium is increasingly recognized as a mechanistic link between cardiovascular risk factors and dementia, including Alzheimer disease. BACE1 (β-site amyloid-β precursor protein-cleaving enzyme 1) is responsible for β-processing of APP (amyloid-β precursor protein), the first step in the production of Aβ (amyloid-β) peptides, major culprits in the pathogenesis of Alzheimer disease. Under pathological conditions, excessive activation of BACE1 exerts detrimental effects on endothelial function by Aβ-dependent and Aβ-independent mechanisms. High local concentration of Aβ in the brain blood vessels is responsible for the loss of key vascular protective functions of endothelial cells. More recent studies recognized significant contribution of Aβ-independent proteolytic activity of endothelial BACE1 to the pathogenesis of endothelial dysfunction. This review critically evaluates existing evidence supporting the concept that excessive activation of BACE1 expressed in the cerebrovascular endothelium impairs key homeostatic functions of the brain blood vessels. This concept has important therapeutic implications. Indeed, improved understanding of the mechanisms of endothelial dysfunction may help in efforts to develop new approaches to the protection and preservation of healthy cerebrovascular function.
Collapse
Affiliation(s)
- Zvonimir S. Katusic
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA
- Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55902, USA
| | - Livius V. d’Uscio
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA
- Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55902, USA
| | - Tongrong He
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA
- Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55902, USA
| |
Collapse
|
|
9
|
Rhea EM, Leclerc M, Yassine HN, Capuano AW, Tong H, Petyuk VA, Macauley SL, Fioramonti X, Carmichael O, Calon F, Arvanitakis Z. State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease. Aging Dis 2024; 15:1688-1725. [PMID: 37611907 PMCID: PMC11272209 DOI: 10.14336/ad.2023.0814] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/14/2023] [Indexed: 08/25/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.
Collapse
Affiliation(s)
- Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA.
| | - Manon Leclerc
- Faculty of Pharmacy, Laval University, Quebec, Quebec, Canada.
- Neuroscience Axis, CHU de Québec Research Center - Laval University, Quebec, Quebec, Canada.
| | - Hussein N Yassine
- Departments of Neurology and Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Ana W Capuano
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
| | - Han Tong
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
| | - Vladislav A Petyuk
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
| | - Shannon L Macauley
- Department of Physiology, University of Kentucky, Lexington, KY 40508, USA.
| | - Xavier Fioramonti
- International Associated Laboratory OptiNutriBrain, Bordeaux, France and Quebec, Canada.
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
| | - Owen Carmichael
- Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
| | - Frederic Calon
- Faculty of Pharmacy, Laval University, Quebec, Quebec, Canada.
- Neuroscience Axis, CHU de Québec Research Center - Laval University, Quebec, Quebec, Canada.
- International Associated Laboratory OptiNutriBrain, Bordeaux, France and Quebec, Canada.
| | - Zoe Arvanitakis
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
| |
Collapse
|
|
10
|
Peng Y, Yao SY, Chen Q, Jin H, Du MQ, Xue YH, Liu S. True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside. Ageing Res Rev 2024; 99:102383. [PMID: 38955264 DOI: 10.1016/j.arr.2024.102383] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/12/2024] [Accepted: 06/17/2024] [Indexed: 07/04/2024]
Abstract
Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aβ, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.
Collapse
Affiliation(s)
- Yong Peng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China.
| | - Shun-Yu Yao
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Quan Chen
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Hong Jin
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Miao-Qiao Du
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Ya-Hui Xue
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| | - Shu Liu
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan, China; Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan, China
| |
Collapse
|
|
11
|
Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
Collapse
Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| |
Collapse
|
|
12
|
Abyadeh M, Gupta V, Paulo JA, Mahmoudabad AG, Shadfar S, Mirshahvaladi S, Gupta V, Nguyen CT, Finkelstein DI, You Y, Haynes PA, Salekdeh GH, Graham SL, Mirzaei M. Amyloid-beta and tau protein beyond Alzheimer's disease. Neural Regen Res 2024; 19:1262-1276. [PMID: 37905874 PMCID: PMC11467936 DOI: 10.4103/1673-5374.386406] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 08/08/2023] [Accepted: 09/07/2023] [Indexed: 11/02/2023] Open
Abstract
ABSTRACT The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.
Collapse
Affiliation(s)
| | - Vivek Gupta
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| | - Joao A. Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Sina Shadfar
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| | - Shahab Mirshahvaladi
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| | - Veer Gupta
- School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Christine T.O. Nguyen
- Department of Optometry and Vision Sciences, School of Health Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - David I. Finkelstein
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Yuyi You
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| | - Paul A. Haynes
- School of Natural Sciences, Macquarie University, Macquarie Park, NSW, Australia
| | - Ghasem H. Salekdeh
- School of Natural Sciences, Macquarie University, Macquarie Park, NSW, Australia
| | - Stuart L. Graham
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| | - Mehdi Mirzaei
- Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Macquarie Park, North Ryde, Sydney, NSW, Australia
| |
Collapse
|
|
13
|
Asthana P, Wong HLX. Preventing obesity, insulin resistance and type 2 diabetes by targeting MT1-MMP. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167081. [PMID: 38367902 DOI: 10.1016/j.bbadis.2024.167081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
Obesity is one of the predominant risk factors for type 2 diabetes. Despite all the modern advances in medicine, an effective drug treatment for obesity without overt side effects has not yet been found. The discovery of growth and differentiation factor 15 (GDF15), an appetite-regulating hormone, created hopes for the treatment of obesity. However, an insufficient understanding of the physiological regulation of GDF15 has been a major obstacle to mitigating GDF15-centric treatment of obesity. Our recent studies revealed how a series of proteolytic events predominantly mediated by membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14), a key cell-surface metalloproteinase involved in extracellular remodeling, contribute to the pathogenesis of metabolic disorders, including obesity and diabetes. The MT1-MMP-mediated cleavage of the GDNF family receptor-α-like (GFRAL), a key neuronal receptor of GDF15, controls the satiety center in the hindbrain, thereby regulating non-homeostatic appetite and bodyweight changes. Furthermore, increased activation of MT1-MMP does not only lead to increased risk of obesity, but also causes age-associated insulin resistance by cleaving Insulin Receptor in major metabolic tissues. Importantly, inhibition of MT1-MMP effectively protects against obesity and diabetes, revealing the therapeutic potential of targeting MT1-MMP for the management of metabolic disorders.
Collapse
Affiliation(s)
- Pallavi Asthana
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
| | | |
Collapse
|
|
14
|
Shen H, Jiang Y, Qiu C, Xie X, Zhang H, He Z, Song Z, Zhou W. Abnormal amyloid precursor protein processing in periodontal tissue in a murine model of periodontitis induced by Porphyromonas gingivalis. J Periodontal Res 2024; 59:395-407. [PMID: 38311599 DOI: 10.1111/jre.13224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 11/27/2023] [Accepted: 12/05/2023] [Indexed: 02/06/2024]
Abstract
OBJECTIVE The study aimed to investigate the change of amyloid precursor protein (APP) processing and amyloid β (Aβ) metabolites in linking periodontitis to Alzheimer's disease (AD). BACKGROUND Aβ is one of the main pathological features of AD, and few studies have discussed changes in its expression in peripheral tissues or analyzed the relationship between the peripheral imbalance of Aβ production and clearance. METHODS A murine model of periodontitis was established by oral infection with Porphyromonas gingivalis (P. gingivalis). Micro-computed tomography (Micro-CT) was used to observe the destruction of the alveolar bone. Nested quantitative polymerase chain reaction (qPCR) was used to measure small quantities of P.gingivalis DNA in different tissues. Behavioral experiments were performed to measure cognitive function in the mice. The mRNA levels of TNF-α, IL-6, IL-8, RANKL, OPG, APP695, APP751, APP770, and BACE1 in the gingival tissues or cortex were detected by RT-PCR. The levels of Aβ1-40 and Aβ1-42 in gingival crevicular fluid (GCF) and plasma were tested by ELISA. RESULTS P. gingivalis oral infection was found to cause alveolar bone resorption and impaired learning and memory. P.gingivalis DNA was detected in the gingiva, blood and cortex of the P.gingivalis group by nested qPCR (p < .05). The mRNA expression of TNF-α, IL-6, IL-8, RANKL/OPG, and BACE1 in the gingival tissue was significantly higher than that in the control group (p < .05). Similarly, upregulated mRNA levels of APP695 and APP770 were observed in the gingival tissuses and cortex of the P. gingivalis group (p < .05). The levels of Aβ1-40 and Aβ1-42 in the GCF and plasma of the P. gingivalis group were significantly higher than those in the control group (p < .05). CONCLUSION P. gingivalis can directly invade the brain via hematogenous infection. The invasion of P. gingivalis could trigger an immune response and lead to an imbalance between Aβ production and clearance in peripheral tissues, which may trigger an abnormal Aβ metabolite in the brain, resulting in the occurrence and development of AD.
Collapse
Affiliation(s)
- Hui Shen
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Yiting Jiang
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Che Qiu
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Xinyi Xie
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Huanyu Zhang
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Zhiyan He
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongchen Song
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Wei Zhou
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
15
|
Zhou J, Singh N, Galske J, Hudobenko J, Hu X, Yan R. BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides. Mol Neurodegener 2023; 18:31. [PMID: 37143090 PMCID: PMC10161466 DOI: 10.1186/s13024-023-00611-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/07/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer's disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions. METHODS We conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates. Similar scRNA-seq was also conducted using AD mice with conditional deletion of Bace1 in the adult stage (5xFAD;Bace1fl/fl;UBC-creER compared to 5xFAD;Bace1fl/fl controls). We compared the transcriptomes of astrocyte and reactive astrocyte clusters and identified several differentially expressed genes, which were further validated using Bace1 KO astrocyte cultures. Mice with astrocyte-specific Bace1 knockout in 5xFAD background were used to compare amyloid deposition. Mechanistic studies using cultured astrocytes were used to identify BACE1 substrates for changes in gene expression and signaling activity. RESULTS Among altered genes, Clusterin (Clu) and Cxcl14 were significantly upregulated and validated by measuring protein levels. Moreover, BACE1 deficiency enhanced both astrocytic Aβ uptake and degradation, and this effect was significantly attenuated by siRNA knockdown of Clu. Mechanistic study suggests that BACE1 deficiency abolishes cleavage of astrocytic insulin receptors (IR), and this may enhance expression of Clu and Cxcl14. Acutely isolated astrocytes from astrocyte-specific knockout of Bace1 mice (Bace1 fl/fl;Gfap-cre) show similar increases in CLU and IR. Furthermore, astrocyte-specific knockout of Bace1 in a 5xFAD background resulted in a significant attenuation in cortical Aβ plaque load through enhanced clearance. CONCLUSION Together, our study suggests that BACE1 in astrocytes regulates expression of Clu and Cxcl14, likely via the control of insulin receptor pathway, and inhibition of astrocytic BACE1 is a potential alternative strategy for enhancing Aβ clearance.
Collapse
Affiliation(s)
- John Zhou
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, United States
- Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, United States
| | - Neeraj Singh
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA
| | - James Galske
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA
| | - Jacob Hudobenko
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA
| | - Xiangyou Hu
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA
| | - Riqiang Yan
- Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA.
| |
Collapse
|
|
16
|
Franklin ZJ, Croce L, Dekeryte R, Delibegovic M, Platt B. BACE cleavage of APP does not drive the diabetic phenotype of PLB4 mice. Neurobiol Dis 2023; 182:106142. [PMID: 37137417 DOI: 10.1016/j.nbd.2023.106142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2DM), two prevalent diseases related to ageing, often share common pathologies including increased inflammation, endoplasmic reticulum (ER) stress, and impaired metabolic homeostasis predominantly affecting different organs. Therefore, it was unexpected to find in a previous study that neuronal hBACE1 knock-in (PLB4 mouse) leads to both an AD- and T2DM- like phenotype. The complexity of this co-morbidity phenotype required a deeper systems approach to explore the age-related changes in AD and T2DM-like pathologies of the PLB4 mouse. Therefore, we here analysed key neuronal and metabolic tissues comparing associated pathologies to those of normal ageing. METHODS Glucose tolerance, insulin sensitivity and protein turnover were assessed in 5-h fasted 3- and 8-month-old male PLB4 and wild-type mice. Western Blot and quantitative PCR were performed to determine regulation of homeostatic and metabolic pathways in insulin-stimulated brain, liver and muscle tissue. RESULTS Neuronal hBACE1 expression caused early pathological cleavage of APP (increased monomeric Aβ (mAβ) levels at 3-months), in parallel with brain ER stress (increased phosphorylation of the translation regulation factor (p-eIF2α) and the chaperone binding immunoglobulin protein (BIP)). However, APP processing shifted over time (higher full-length APP and sAPPβ levels, alongside lower mAβ and secreted APPα at 8 months), along with increased ER stress (phosphorylated/total inositol-requiring enzyme 1α (IRE1α)) in brain and liver. Metabolically, systemic glucose intolerance was evident from 3 months, yet metabolic signalling varied greatly between tissues and ages, and was confined to the periphery (muscle insulin receptors (IR), dipeptidyl-peptidase-4 (DPP4) levels, and decreased phosphorylated protein Kinase B (p-Akt), alongside increased liver DPP4 and fibroblast growth factor 21 (FGF21)), all of which normalised to wild-type levels at 8 months. CONCLUSION Our data suggest that the murine nervous system is affected early by APP misprocessing as a result of hBACE1 introduction, which coincided with ER stress, but not IR changes, and was alleviated with age. Peripheral metabolic alterations occurred early and revealed tissue-specific (liver vs. muscle) adaptations in metabolic markers but did not correlate with neuronal APP processing. Compensatory vs. contributory neuronal mechanisms associated with hBACE1 expression at different ages may explain why mice intrinsically do not develop AD pathologies and may offer new insights for future interventions.
Collapse
Affiliation(s)
- Z J Franklin
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - L Croce
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - R Dekeryte
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - M Delibegovic
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
| | - B Platt
- Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
| |
Collapse
|
|
17
|
Müller SA, Shmueli MD, Feng X, Tüshaus J, Schumacher N, Clark R, Smith BE, Chi A, Rose-John S, Kennedy ME, Lichtenthaler SF. The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener 2023; 18:13. [PMID: 36810097 PMCID: PMC9942414 DOI: 10.1186/s13024-023-00596-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 01/11/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. METHODS To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. CONCLUSION BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.
Collapse
Affiliation(s)
- Stephan A Müller
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Merav D Shmueli
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Xiao Feng
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Johanna Tüshaus
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | | | - Ryan Clark
- Neuroscience, Merck & Co. Inc., Boston, MA, USA
| | - Brad E Smith
- Laboratory Animal Resources, Merck & Co. Inc., West Point, PA, USA
| | - An Chi
- Chemical Biology, Merck & Co. Inc., Boston, MA, USA
| | | | | | - Stefan F Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. .,Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. .,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
| |
Collapse
|
|
18
|
Bao H, Shen Y. Unmasking BACE1 in aging and age-related diseases. Trends Mol Med 2023; 29:99-111. [PMID: 36509631 DOI: 10.1016/j.molmed.2022.11.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/14/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022]
Abstract
The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) has long been considered a conventional target for Alzheimer's disease (AD). Unfortunately, AD clinical trials of most BACE1 inhibitors were discontinued due to ineffective cognitive improvement or safety challenges. Recent studies investigating the involvement of BACE1 in metabolic, vascular, and immune functions have indicated a role in aging, diabetes, hypertension, and cancer. These novel BACE1 functions have helped to identify new 'druggable' targets for BACE1 against aging comorbidities. In this review, we discuss BACE1 regulation during aging, and then provide recent insights into its enzymatic and nonenzymatic involvement in aging and age-related diseases. Our study not only proposes the perspective of BACE1's actions in various systems, but also provides new directions for using BACE1 inhibitors and modulators to delay aging and to treat age-related diseases.
Collapse
Affiliation(s)
- Hong Bao
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yong Shen
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Provincial Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, 230026, China; CAS Key Laboratory of Brain Function and Disease, Division of Biological and Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
| |
Collapse
|
|
19
|
Leclerc M, Bourassa P, Tremblay C, Caron V, Sugère C, Emond V, Bennett DA, Calon F. Cerebrovascular insulin receptors are defective in Alzheimer's disease. Brain 2023; 146:75-90. [PMID: 36280236 PMCID: PMC9897197 DOI: 10.1093/brain/awac309] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/24/2022] [Accepted: 08/12/2022] [Indexed: 01/11/2023] Open
Abstract
Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined. Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer's disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer's disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood-brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer's disease neuropathology induces insulin resistance at the level of the blood-brain barrier. Overall, the present data in post-mortem Alzheimer's disease brains and an animal model of Alzheimer's disease indicate that defects in the insulin receptor localized at the blood-brain barrier strongly contribute to brain insulin resistance in Alzheimer's disease, in association with β-amyloid pathology.
Collapse
Affiliation(s)
- Manon Leclerc
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
| | - Philippe Bourassa
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Cyntia Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Vicky Caron
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Camille Sugère
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Vincent Emond
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - David A Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
| | - Frédéric Calon
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
| |
Collapse
|
|
20
|
Hughes TM, Craft S. Cerebral insulin receptors: a nexus for vascular and metabolic contributions to Alzheimer's disease. Brain 2023; 146:8-9. [PMID: 36402144 DOI: 10.1093/brain/awac433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 11/17/2022] [Indexed: 11/21/2022] Open
Abstract
This scientific commentary refers to ‘Cerebrovascular insulin receptors are defective in Alzheimer’s disease’ by Leclerc et al. (https://doi.org/10.1093/brain/awac309).
Collapse
Affiliation(s)
- Timothy M Hughes
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Suzanne Craft
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| |
Collapse
|
|
21
|
Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer's Disease-like Neuropathology in a Mouse Model for Down Syndrome. Antioxidants (Basel) 2023; 12:antiox12010111. [PMID: 36670973 PMCID: PMC9854894 DOI: 10.3390/antiox12010111] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023] Open
Abstract
Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.
Collapse
|
|
22
|
Zhang X, Zhu X, Bi X, Huang J, Zhou L. The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides. Int J Mol Sci 2022; 23:7793. [PMID: 35887136 PMCID: PMC9325136 DOI: 10.3390/ijms23147793] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/04/2023] Open
Abstract
The insulin receptor (IR) is a transmembrane protein that is activated by ligands in insulin signaling pathways. The IR has been considered as a novel therapeutic target for clinical intervention, considering the overexpression of its protein and A-isoform in multiple cancers, Alzheimer's disease, and Type 2 diabetes mellitus in humans. Meanwhile, it may also serve as a potential target in pest management due to its multiple physiological influences in insects. In this review, we provide an overview of the structural and molecular biology of the IR, functions of IRs in humans and insects, physiological and nonpeptide small molecule modulators of the IR, and the regulating mechanisms of the IR. Xenobiotic compounds and the corresponding insecticidal chemicals functioning on the IR are also discussed. This review is expected to provide useful information for a better understanding of human IR-related diseases, as well as to facilitate the development of novel small-molecule activators and inhibitors of the IR for use as medicines or pesticides.
Collapse
Affiliation(s)
| | | | | | - Jiguang Huang
- Key Laboratory of Natural Pesticides & Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (X.Z.); (X.B.)
| | - Lijuan Zhou
- Key Laboratory of Natural Pesticides & Chemical Biology, Ministry of Education, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (X.Z.); (X.B.)
| |
Collapse
|
|
23
|
Taylor HA, Przemylska L, Clavane EM, Meakin PJ. BACE1: More than just a β-secretase. Obes Rev 2022; 23:e13430. [PMID: 35119166 PMCID: PMC9286785 DOI: 10.1111/obr.13430] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/04/2022] [Accepted: 01/16/2022] [Indexed: 02/06/2023]
Abstract
β-site amyloid precursor protein cleaving enzyme-1 (BACE1) research has historically focused on its actions as the β-secretase responsible for the production of β-amyloid beta, observed in Alzheimer's disease. Although the greatest expression of BACE1 is found in the brain, BACE1 mRNA and protein is also found in many cell types including pancreatic β-cells, adipocytes, hepatocytes, and vascular cells. Pathologically elevated BACE1 expression in these cells has been implicated in the development of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease. In this review, we examine key questions surrounding the BACE1 literature, including how is BACE1 regulated and how dysregulation may occur in disease, and understand how BACE1 regulates metabolism via cleavage of a myriad of substrates. The phenotype of the BACE1 knockout mice models, including reduced weight gain, increased energy expenditure, and enhanced leptin signaling, proposes a physiological role of BACE1 in regulating energy metabolism and homeostasis. Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology. Finally, this review aims to examine the possibility that BACE1 inhibitors could provide a innovative treatment for obesity and its comorbidities.
Collapse
Affiliation(s)
- Hannah A Taylor
- Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Lena Przemylska
- Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Eva M Clavane
- Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Paul J Meakin
- Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| |
Collapse
|
|
24
|
Guo X, Asthana P, Gurung S, Zhang S, Wong SKK, Fallah S, Chow CFW, Che S, Zhai L, Wang Z, Ge X, Jiang Z, Wu J, Zhang Y, Wu X, Xu K, Lin CY, Kwan HY, Lyu A, Zhou Z, Bian ZX, Wong HLX. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat Commun 2022; 13:3749. [PMID: 35768470 PMCID: PMC9242991 DOI: 10.1038/s41467-022-31563-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 06/22/2022] [Indexed: 12/24/2022] Open
Abstract
Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes.
Collapse
Affiliation(s)
- Xuanming Guo
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Pallavi Asthana
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Susma Gurung
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Shuo Zhang
- grid.194645.b0000000121742757School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Sheung Kin Ken Wong
- grid.194645.b0000000121742757School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Samane Fallah
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Chi Fung Willis Chow
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China ,grid.419537.d0000 0001 2113 4567Centre for Systems Biology Dresden, Max Planck Institute for Molecular Cell and Biology, Dresden, Germany
| | - Sijia Che
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Lixiang Zhai
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Zening Wang
- grid.267308.80000 0000 9206 2401Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX USA
| | - Xin Ge
- grid.267308.80000 0000 9206 2401Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX USA
| | - Zhixin Jiang
- grid.194645.b0000000121742757School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Jiayan Wu
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yijing Zhang
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Xiaoyu Wu
- grid.470187.dRespiratory Department, Jinhua Guangfu hospital, Jinhua, China
| | - Keyang Xu
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Cheng Yuan Lin
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China ,grid.221309.b0000 0004 1764 5980Centre for Chinese Herbal Medicine Drug Development Limited, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hiu Yee Kwan
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Aiping Lyu
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Zhongjun Zhou
- grid.194645.b0000000121742757School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China
| | - Zhao-Xiang Bian
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China ,grid.221309.b0000 0004 1764 5980Centre for Chinese Herbal Medicine Drug Development Limited, Hong Kong Baptist University, Hong Kong SAR, China
| | - Hoi Leong Xavier Wong
- grid.221309.b0000 0004 1764 5980School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| |
Collapse
|
|
25
|
Verouti SN, Pujol-Giménez J, Bermudez-Lekerika P, Scherler L, Bhardwaj R, Thomas A, Lenglet S, Siegrist M, Hofstetter W, Fuster DG, Hediger MA, Escher G, Vogt B. The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance. Front Physiol 2022; 13:912277. [PMID: 35784893 PMCID: PMC9240775 DOI: 10.3389/fphys.2022.912277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/18/2022] [Indexed: 12/12/2022] Open
Abstract
The metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed in vitro the transport properties of mutant ZIP8 A391T and investigated in vivo in mice the physiological effects of this polymorphism. In vitro, the intrinsic transport properties of mutant ZIP8 were similar to those of wild type ZIP8, but cellular uptake of zinc, cadmium and iron was attenuated due to reduced ZIP8 plasma membrane expression. We then generated the ZIP8 A393T mice (ZIP8KI) that carry the corresponding polymorphism and characterized their phenotype. We observed lower protein expression in lung and kidney membrane extracts in ZIP8KI mice. The ZIP8KI mice exhibited striking changes in metal ion composition of the tissues, including cobalt, palladium, mercury and platinum. In agreement with GWAS, ZIP8KI mice showed reduced arterial blood pressure. Body weight and plasma lipid composition remained unchanged, although these features were reported to be increased in GWAS. ZIP8KI mice also exhibited remarkable insulin resistance and were protected from elevated blood glucose when challenged by dietary sucrose supplementation. We showed that increased hepatic insulin receptor expression and decreased ZnT8 (slc30a8) metal ion transporter mRNA expression are associated with this phenotypic change. In conclusion, our data reveal that ZIP8 plays an important role in blood pressure regulation and glucose homeostasis.
Collapse
Affiliation(s)
- Sophia N. Verouti
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jonai Pujol-Giménez
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Paola Bermudez-Lekerika
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Laeticia Scherler
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Rajesh Bhardwaj
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, United States
| | - Aurélien Thomas
- Forensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University, Geneva, Switzerland
- Faculty Unit of Toxicology, CURML, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Sébastien Lenglet
- Forensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University, Geneva, Switzerland
| | - Mark Siegrist
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Willy Hofstetter
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Daniel G. Fuster
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Matthias A. Hediger
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- *Correspondence: Matthias A. Hediger, ; Geneviève Escher, ; Bruno Vogt,
| | - Geneviève Escher
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- *Correspondence: Matthias A. Hediger, ; Geneviève Escher, ; Bruno Vogt,
| | - Bruno Vogt
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- *Correspondence: Matthias A. Hediger, ; Geneviève Escher, ; Bruno Vogt,
| |
Collapse
|
|
26
|
Taylor HA, Simmons KJ, Clavane EM, Trevelyan CJ, Brown JM, Przemyłska L, Watt NT, Matthews LC, Meakin PJ. PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer's Disease: A Data Mining and Bioinformatics Study. Int J Mol Sci 2022; 23:ijms23094568. [PMID: 35562959 PMCID: PMC9103286 DOI: 10.3390/ijms23094568] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/15/2022] [Accepted: 04/18/2022] [Indexed: 02/04/2023] Open
Abstract
The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer's disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aβ concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD.
Collapse
Affiliation(s)
- Hannah A. Taylor
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Katie J. Simmons
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Eva M. Clavane
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Christopher J. Trevelyan
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Jane M. Brown
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Lena Przemyłska
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Nicole T. Watt
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
| | - Laura C. Matthews
- Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK;
| | - Paul J. Meakin
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK; (H.A.T.); (K.J.S.); (E.M.C.); (C.J.T.); (J.M.B.); (L.P.); (N.T.W.)
- Correspondence:
| |
Collapse
|
|
27
|
Zhang S, Bai P, Lei D, Liang Y, Zhen S, Bakiasi G, Pang H, Choi SH, Wang C, Tanzi RE, Zhang C. Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models. J Biol Chem 2022; 298:101794. [PMID: 35248531 PMCID: PMC8958546 DOI: 10.1016/j.jbc.2022.101794] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through the targeting of epigenetic pathways. Recently, emerging evidence from preclinical studies suggested the potential in developing therapeutics of Alzheimer's disease (AD) by targeting bromodomain containing protein 4 (BRD4), an epigenetic regulatory protein. However, further characterization of AD-related pathological events is urgently required. Here, we investigated the effects of pharmacological degradation or inhibition of BRD4 on AD cell models. Interestingly, we found that both degradation and inhibition of BRD4 by ARV-825 and JQ1, respectively, robustly increased the levels of amyloid-beta (Aβ), which has been associated with the neuropathology of AD. Subsequently, we characterized the mechanisms by which downregulation of BRD4 increases Aβ levels. We found that both degradation and inhibition of BRD4 increased the levels of BACE1, the enzyme responsible for cleavage of the amyloid-beta protein precursor (APP) to generate Aβ. Consistent with Aβ increase, we also found that downregulation of BRD4 increased AD-related phosphorylated Tau (pTau) protein in our 3D-AD human neural cell culture model. Therefore, our results suggest that downregulation of BRD4 would not be a viable strategy for AD intervention. Collectively, our study not only shows that BRD4 is a novel epigenetic component that regulates BACE1 and Aβ levels, but also provides novel and translational insights into the targeting of BRD4 for potential clinical applications.
Collapse
Affiliation(s)
- Siyi Zhang
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; Department of Forensic Medicine, China Medical University, Shenyang, China
| | - Ping Bai
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Dan Lei
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Yingxia Liang
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Sherri Zhen
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Grisilda Bakiasi
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Hao Pang
- Department of Forensic Medicine, China Medical University, Shenyang, China
| | - Se Hoon Choi
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Changning Wang
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Can Zhang
- Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
| |
Collapse
|
|
28
|
Abstract
The cerebral accumulation of amyloid β (Aβ) is a hallmark of Alzheimer’s disease (AD). While type 2 diabetes mellitus is known to be a risk factor for AD, the underlying mechanisms remain unclear. In the present study, we demonstrate that plasma Aβ is produced from glucose- and insulin-susceptible peripheral tissues, such as the pancreas, adipose tissues, skeletal muscles, and liver, to inhibit insulin secretion from islet β-cells. Our findings suggest a physiological role of peripheral Aβ in glucose and insulin metabolism and a possible mechanism linking diabetes to AD. In addition, although plasma Aβ levels are currently used as a diagnostic biomarker of AD, our data suggest they should be used with caution. Type 2 diabetes mellitus is known to be a risk factor for Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. In AD, the cerebral accumulation of amyloid β (Aβ) triggers a pathological cascade leading to neurodegeneration. Plasma Aβ levels are thought to reflect the brain amyloid pathology and currently used as a diagnostic biomarker of AD. However, amyloid precursor protein and Aβ-generating enzymes, β- and γ-secretases, are widely expressed in various peripheral tissues. Previous reports have shown that glucose and insulin loading cause a transient increase of plasma Aβ in mice and humans. These findings led us to speculate that plasma Aβ is produced from glucose- and insulin-susceptible peripheral tissues to play a role in glucose and insulin metabolism. To test this hypothesis, we investigated the effects of glucose and insulin on Aβ secretion and the effect of Aβ on insulin secretion in vivo, ex vivo, and in vitro. Aβ was found to be secreted from β-cells of the pancreas along with insulin upon glucose stimulation. Upon insulin stimulation, Aβ was secreted from cells of insulin-targeted organs, such as adipose tissues, skeletal muscles, and the liver, along with their organokines. Furthermore, Aβ inhibited the glucose-triggered insulin secretion from β-cells, slowing down glucose clearance from the blood. These results suggest that peripheral Aβ acts as a negative modulator of insulin secretion. Our findings provide a possible mechanism linking diabetes to AD and call attention to how plasma Aβ levels are used in AD diagnosis.
Collapse
|
|
29
|
Murgia N, Ma Y, Najam SS, Liu Y, Przybys J, Guo C, Konopka W, Vinnikov IA. In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity. Front Endocrinol (Lausanne) 2022; 13:867929. [PMID: 35873003 PMCID: PMC9302447 DOI: 10.3389/fendo.2022.867929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity is a growing medical and social problem worldwide. The control of energy homeostasis in the brain is achieved by various regions including the arcuate hypothalamic nucleus (ARH). The latter comprises a number of neuronal populations including the first order metabolic neurons, appetite-stimulating agouti-related peptide (AgRP) neurons and appetite-suppressing proopiomelanocortin (POMC) neurons. Using an in vivo reductionist approach and POMCCre-dependent CRISPR-Cas9, we demonstrate that miR-15a-5p protects from obesity. Moreover, we have identified Bace1, a gene previously linked to energy metabolism imbalance, as a direct target of miR-15a-5p. This work warrants further investigations of non-coding RNA-mediated regulation of energy homeostasis and might contribute to the development of novel therapeutic approaches to treat metabolic diseases.
Collapse
Affiliation(s)
- Nicola Murgia
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Ma
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Syeda Sadia Najam
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Liu
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Joanna Przybys
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Chenkai Guo
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Witold Konopka
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
- Laboratory of Neuroplasticity and Metabolism, Department of Life Sciences and Biotechnology, Łukasiewicz PORT Polish Center for Technology Development, Wrocław, Poland
| | - Ilya A. Vinnikov
- Laboratory of Molecular Neurobiology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Ilya A. Vinnikov,
| |
Collapse
|
|
30
|
Dai L, Shen Y. Insights into T-cell dysfunction in Alzheimer's disease. Aging Cell 2021; 20:e13511. [PMID: 34725916 PMCID: PMC8672785 DOI: 10.1111/acel.13511] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/22/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022] Open
Abstract
T cells, the critical immune cells of the adaptive immune system, are often dysfunctional in Alzheimer's disease (AD) and are involved in AD pathology. Reports highlight neuroinflammation as a crucial modulator of AD pathogenesis, and aberrant T cells indirectly contribute to neuroinflammation by secreting proinflammatory mediators via direct crosstalk with glial cells infiltrating the brain. However, the mechanisms underlying T‐cell abnormalities in AD appear multifactorial. Risk factors for AD and pathological hallmarks of AD have been tightly linked with immune responses, implying the potential regulatory effects of these factors on T cells. In this review, we discuss how the risk factors for AD, particularly Apolipoprotein E (ApoE), Aβ, α‐secretase, β‐secretase, γ‐secretase, Tau, and neuroinflammation, modulate T‐cell activation and the association between T cells and pathological AD hallmarks. Understanding these associations is critical to provide a comprehensive view of appropriate therapeutic strategies for AD.
Collapse
Affiliation(s)
- Linbin Dai
- Institute on Aging and Brain Disorders The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Sciences and Technology of China Hefei China
- Neurodegenerative Disease Research Center University of Science and Technology of China Hefei China
- Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Hefei China
| | - Yong Shen
- Institute on Aging and Brain Disorders The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Sciences and Technology of China Hefei China
- Neurodegenerative Disease Research Center University of Science and Technology of China Hefei China
- Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Hefei China
| |
Collapse
|
|
31
|
Dai L, Wang Q, Lv X, Gao F, Chen Z, Shen Y. Elevated β-secretase 1 expression mediates CD4 + T cell dysfunction via PGE2 signalling in Alzheimer's disease. Brain Behav Immun 2021; 98:337-348. [PMID: 34500034 DOI: 10.1016/j.bbi.2021.08.234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/20/2021] [Accepted: 08/28/2021] [Indexed: 01/06/2023] Open
Abstract
Circulating CD4+ T cells are dysfunctional in Alzheimer's disease (AD), however, the underlying molecular mechanisms are not clear. In this study, we demonstrate that CD4+ T cells from AD patients and 5xFAD transgenic mice exhibit elevated levels of β-secretase 1 (BACE1). Overexpression of BACE1 in CD4+ T cells potentiated CD4+ T-cell activation and T-cell-dependent immune responses. Mechanistically, BACE1 modulates prostaglandin E2 (PGE2) synthetase-microsomal prostaglandin E synthase 2 (mPGES2)-to promote mPGES2 maturation and PGE2 production, which increases T-cell receptor (TCR) signalling. Moreover, administration of peripheral PGE2 signalling antagonists partially ameliorates CD4+ T cell overactivation and AD pathology in 5xFAD mice. Overall, our results reveal a potential role for BACE1 in mediating CD4+ T-cell dysfunction in AD.
Collapse
Affiliation(s)
- Linbin Dai
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Qiong Wang
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Xinyi Lv
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Feng Gao
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Zuolong Chen
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Yong Shen
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Centre, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China; Centre for Excellence in Brain Sciences and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
| |
Collapse
|
|
32
|
Gaborit B, Govers R, Altié A, Brunel JM, Morange P, Peiretti F. The aminosterol Claramine inhibits β-secretase 1-mediated insulin receptor cleavage. J Biol Chem 2021; 297:100818. [PMID: 34029592 PMCID: PMC8254121 DOI: 10.1016/j.jbc.2021.100818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 12/05/2022] Open
Abstract
The cleavage of the insulin receptor by β-secretase 1 (BACE1) in the liver increases during diabetes, which contributes to reduce insulin receptor levels and impair insulin signaling. However, the precise signaling events that lead to this increased cleavage are unclear. We showed that BACE1 cleaves the insulin receptor in the early secretory pathway. Indeed, coimmunoprecipitation experiments reveal the interaction of the proforms of the two proteins. Moreover, fragments of insulin receptor are detected in the early secretory pathway and a mutated form of BACE1 that retains its prodomain cleaves an early secretory pathway-resident form of the insulin receptor. We showed that BACE1 proform levels are regulated by proteasome and/or lysosome-dependent degradation systems whose efficiencies are dependent on the O-GlcNacylation process. Our results showed that enhanced O-GlcNacylation reduces the efficiency of intracellular protein degradation systems, leading to the accumulation of the proform of BACE1 in the early secretory pathway where it cleaves the precursor of the insulin receptor. All these dysregulations are found in the livers of diabetic mice. In addition, we performed a screen of molecules according to their ability to increase levels of the insulin receptor at the surface of BACE1-overexpressing cells. This approach identified the aminosterol Claramine, which accelerated intracellular trafficking of the proform of BACE1 and increased autophagy. Both of these effects likely contribute to the reduced amount of the proform of BACE1 in the early secretory pathway, thereby reducing insulin receptor cleavage. These newly described properties of Claramine are consistent with its insulin sensitizing effect.
Collapse
Affiliation(s)
- Bénédicte Gaborit
- INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France; Endocrinology, Metabolic Diseases and Nutrition Department, APHM, Marseille, France
| | - Roland Govers
- INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France
| | - Alexandre Altié
- INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France
| | | | - Pierre Morange
- INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France; Hematology Laboratory, La Timone Hospital, APHM, Marseille, France
| | - Franck Peiretti
- INSERM, INRAE, C2VN, Aix Marseille University, Marseille, France.
| |
Collapse
|
|
33
|
Huang X, Pan L, Zuo Z, Li M, Zeng L, Li R, Ye Y, Zhang J, Wu G, Bai R, Zhuang L, Wei L, Zheng Y, Su J, Deng J, Deng S, Zhang S, Zhu S, Che X, Wang C, Wu C, Chen R, Lin D, Zheng J. LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling. Nat Commun 2021; 12:3830. [PMID: 34158490 PMCID: PMC8219694 DOI: 10.1038/s41467-021-23904-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
The molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.
Collapse
Affiliation(s)
- Xudong Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ling Pan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhixiang Zuo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mei Li
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lingxing Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rui Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ying Ye
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jialiang Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Guandi Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ruihong Bai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lisha Zhuang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lusheng Wei
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanfen Zheng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiachun Su
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Junge Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shuang Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shaoping Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shihao Zhu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xu Che
- Department of Abdominal Surgery, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengfeng Wang
- Department of Abdominal Surgery, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rufu Chen
- Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Dongxin Lin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jian Zheng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| |
Collapse
|
|
34
|
Serum Amyloid Beta42 Is Not Eliminated by the Cirrhotic Liver: A Pilot Study. J Clin Med 2021; 10:jcm10122669. [PMID: 34204545 PMCID: PMC8235170 DOI: 10.3390/jcm10122669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Amyloid-beta (Aβ) deposition in the brain is the main pathological hallmark of Alzheimer disease. Peripheral clearance of Aβ may possibly also lower brain levels. Recent evidence suggested that hepatic clearance of Aβ42 is impaired in liver cirrhosis. To further test this hypothesis, serum Aβ42 was measured by ELISA in portal venous serum (PVS), systemic venous serum (SVS), and hepatic venous serum (HVS) of 20 patients with liver cirrhosis. Mean Aβ42 level was 24.7 ± 20.4 pg/mL in PVS, 21.2 ± 16.7 pg/mL in HVS, and 19.2 ± 11.7 pg/mL in SVS. Similar levels in the three blood compartments suggested that the cirrhotic liver does not clear Aβ42. Aβ42 was neither associated with the model of end-stage liver disease score nor the Child–Pugh score. Patients with abnormal creatinine or bilirubin levels or prolonged prothrombin time did not display higher Aβ42 levels. Patients with massive ascites and patients with large varices had serum Aβ42 levels similar to patients without these complications. Serum Aβ42 was negatively associated with connective tissue growth factor levels (r = −0.580, p = 0.007) and a protective role of Aβ42 in fibrogenesis was already described. Diabetic patients with liver cirrhosis had higher Aβ42 levels (p = 0.069 for PVS, p = 0.047 for HVS and p = 0.181 for SVS), which is in accordance with previous reports. Present analysis showed that the cirrhotic liver does not eliminate Aβ42. Further studies are needed to explore the association of liver cirrhosis, Aβ42 levels, and cognitive dysfunction.
Collapse
|
|
35
|
Shi Y, Gao F, Yang X, Liu D, Han Q, Liu Z, Zhu H, Shen Y. Increase of BACE1, Brain-Renal Risk Factor, Contributes to Kidney Damage in an Alzheimer's Disease Mouse Model. J Alzheimers Dis 2021; 76:237-248. [PMID: 32444547 DOI: 10.3233/jad-200204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND It is believed that there is a certain correlation between the brain and kidneys, but it is poorly understood. Many findings suggested that there were previously unknown signaling pathways involving AβPP and BACE1 in the kidney. OBJECTIVE Exploring the changes of BACE1 activity in APP23 mouse kidneys, providing evidence for the function of AβPP and BACE1 activity in the kidney. METHODS The activity and expression of BACE1 were detected in the kidney of APP23 mice by enzymatic assay and western blotting. The protein expression levels of AβPP, claudin1, occludin, VE-cadherin, and Klotho (membrane-form klotho) were examined by using western blotting. The renal pathological changes of APP23 mice were examined by the routine renal pathological procedures. RESULTS In this study, we found that the AβPP protein level was increased in kidneys of APP23 mice compared with wild-type (WT) mice. Additionally, the activity and expression of BACE1 were increased in kidneys of APP23 mice compared to that of WT. BACE1 was predominantly distributed on the lumen side of renal tubular epithelial cells. The protein levels of Klotho and VE-cadherin were decreased, occludin expression was also decreased, and claudin-1 expression was increased. Renal pathological damage which observed in kidneys of APP23 mice was more serious than that in kidneys of WT mice. CONCLUSION Our findings suggest that the increase of AβPP protein levels under Thy-1 neuron promoter in the APP23 mice promoted the increase of renal BACE1 expression and enzymatic activity in the kidneys. Moreover, certain pathological damage in the kidneys of APP23 mice were observed. APP23 mice are easily affected by external risk factors compared with WT mice.
Collapse
Affiliation(s)
- Yan Shi
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing, China.,Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Research Institute of Nephrology, Zhengzhou University, Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Feng Gao
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China.,Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoli Yang
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China.,Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Research Institute of Nephrology, Zhengzhou University, Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Qiuxia Han
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing, China.,Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Research Institute of Nephrology, Zhengzhou University, Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Research Institute of Nephrology, Zhengzhou University, Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, China
| | - Hanyu Zhu
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Beijing, China
| | - Yong Shen
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China.,Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
36
|
Huang H. Proteolytic Cleavage of Receptor Tyrosine Kinases. Biomolecules 2021; 11:biom11050660. [PMID: 33947097 PMCID: PMC8145142 DOI: 10.3390/biom11050660] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/15/2021] [Accepted: 04/26/2021] [Indexed: 01/18/2023] Open
Abstract
The receptor tyrosine kinases (RTKs) are a large family of cell-surface receptors, which are essential components of signal transduction pathways. There are more than fifty human RTKs that can be grouped into multiple RTK subfamilies. RTKs mediate cellular signaling transduction, and they play important roles in the regulation of numerous cellular processes. The dysregulation of RTK signaling is related to various human diseases, including cancers. The proteolytic cleavage phenomenon has frequently been found among multiple receptor tyrosine kinases. More and more information about proteolytic cleavage in RTKs has been discovered, providing rich insight. In this review, we summarize research about different aspects of RTK cleavage, including its relation to cancer, to better elucidate this phenomenon. This review also presents proteolytic cleavage in various members of the RTKs.
Collapse
Affiliation(s)
- Hao Huang
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; or
- Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
37
|
Dekeryte R, Franklin Z, Hull C, Croce L, Kamli-Salino S, Helk O, Hoffmann PA, Yang Z, Riedel G, Delibegovic M, Platt B. The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166149. [PMID: 33892080 DOI: 10.1016/j.bbadis.2021.166149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/18/2021] [Accepted: 04/13/2021] [Indexed: 11/24/2022]
Abstract
AIM The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid β (Aβ) generation in the brain, the key hallmark of Alzheimer's disease (AD). However, recent studies provided evidence that BACE1 also plays a crucial role in metabolic regulation, and we have shown that neuronal human BACE1 knock-in mice (PLB4) display type 2 diabetes mellitus (T2DM)-like symptoms alongside AD-like impairments. Hence, we here investigated if targeted BACE1 inhibition using LY2886721, an active site BACE1 inhibitor, would improve glucose homeostasis, insulin sensitivity and motor performance in PLB4 mice. MATERIALS AND METHODS LY2886721 was administered as a dietary supplement (0.02% wt/wt) for six consecutive weeks. Physiological, metabolic and motor assessments were performed during the last two weeks of treatment, followed by molecular tissue analyses post-mortem. RESULTS LY2886721 treatment improved glucose homeostasis and hepatic gluconeogenesis in diabetic PLB4 mice, as determined by improvements in basal glucose and glucose/pyruvate tolerance tests. Furthermore, LY2886721 improved hepatic insulin sensitivity, as indicated by enhanced basal hyperphosphorylation of insulin receptors. In PLB4 brains, we detected altered basal conditions of APP expression and processing, with beneficial effects on APP processing achieved by LY2886721 treatment. No improvements in motor coordination were found. CONCLUSIONS Our data provide support for a role of BACE1 as a regulator of systemic glucose homeostasis and suggest BACE1 inhibitors for the treatment of T2DM-associated pathologies, especially in cases where diabetes is comorbid to AD.
Collapse
Affiliation(s)
- Ruta Dekeryte
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Zara Franklin
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Claire Hull
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Lorenzo Croce
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Sarah Kamli-Salino
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Oliver Helk
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Philip A Hoffmann
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Zhixiang Yang
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Gernot Riedel
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK
| | - Mirela Delibegovic
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK.
| | - Bettina Platt
- Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK.
| |
Collapse
|
|
38
|
Sajan MP, Hansen BC, Acevedo‐Duncan M, Kindy MS, Cooper DR, Farese RV. Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin-resistant forms of obesity and type 2 diabetes mellitus. MedComm (Beijing) 2021; 2:3-16. [PMID: 34766133 PMCID: PMC8491214 DOI: 10.1002/mco2.54] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 12/21/2020] [Accepted: 12/28/2020] [Indexed: 11/10/2022] Open
Abstract
Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin-angiotensin-adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.
Collapse
Affiliation(s)
- Mini P. Sajan
- Department of Internal MedicineUniversity of South Florida College of MedicineTampaFloridaUSA
- Research ServiceJames AHaley Veterans Administration Medical CenterTampaFloridaUSA
| | - Barbara C. Hansen
- Department of Internal MedicineUniversity of South Florida College of MedicineTampaFloridaUSA
| | - Mildred Acevedo‐Duncan
- Department of ChemistryCollege of Arts and SciencesUniversity of South FloridaTampaFloridaUSA
| | - Mark S. Kindy
- Research ServiceJames AHaley Veterans Administration Medical CenterTampaFloridaUSA
- Department of Pharmaceutical SciencesCollege of PharmacyUniversity of South FloridaTampaFloridaUSA
| | - Denise R. Cooper
- Research ServiceJames AHaley Veterans Administration Medical CenterTampaFloridaUSA
- Department of Molecular MedicineUniversity of South FloridaTampaFloridaUSA
| | - Robert V. Farese
- Department of Internal MedicineUniversity of South Florida College of MedicineTampaFloridaUSA
- Research ServiceJames AHaley Veterans Administration Medical CenterTampaFloridaUSA
| |
Collapse
|
|
39
|
Guo Y, Wang Q, Chen S, Xu C. Functions of amyloid precursor protein in metabolic diseases. Metabolism 2021; 115:154454. [PMID: 33248065 DOI: 10.1016/j.metabol.2020.154454] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 11/02/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Amyloid precursor protein (APP) is a transmembrane precursor protein that is widely expressed in the central nervous system and peripheral tissues in the liver and pancreas, adipose tissue, and myotubes. APP can be cleaved by proteases in two different ways to produce a variety of short peptides, each with different physiological properties and functions. APP peptides generated by non-amyloidogenic processing can positively influence metabolism, while the peptides produced by amyloidogenic processing have the opposite effects. Here, we summarize the regulatory effects of APP and its cleavage peptides on metabolism in the central nervous system and peripheral tissues. In addition, abnormal expression and function of APP and APP-derived peptides are associated with metabolic diseases, such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and cardiovascular disease, and cancers. Pharmacological intervention of APP function or reduction of the production of peptides derived from amyloidogenic processing may be effective strategies for the prevention and treatment of Alzheimer's disease, and they may also provide new guidance for the treatment of metabolic diseases.
Collapse
Affiliation(s)
- Yanjun Guo
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qinqiu Wang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shenghui Chen
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| |
Collapse
|
|
40
|
Wen W, Li P, Liu P, Xu S, Wang F, Huang JH. Post-Translational Modifications of BACE1 in Alzheimer's Disease. Curr Neuropharmacol 2021; 20:211-222. [PMID: 33475074 PMCID: PMC9199555 DOI: 10.2174/1570159x19666210121163224] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/27/2020] [Accepted: 01/21/2021] [Indexed: 11/23/2022] Open
Abstract
Beta-Amyloid Cleaving Enzyme1 (BACE1) is a monospecific enzyme for the key rate-limiting step in the synthesis of beta-amyloid(Aβ) from cleavage of amyloid precursor protein (APP), to form senile plaques and causes cognitive dysfunction in Alzheimer's disease (AD). Post-translation modifications of BACE1, such as acetylation, glycosylation, palmitoylation, phosphorylation, play a crucial role in the trafficking and maturation process of BACE1. The study of BACE1 is of great importance not only for understanding the formation of toxic Aβ but also for the development of an effective therapeutic target for the treatment of AD. This paper review recent advances in the studies about BACE1, with focuses being paid to the relationship of Aβ, BACE1 with post- translational regulation of BACE1. In addition, we specially reviewed studies about the compounds that can be used to affect post-translational regulation of BACE1 or regulate BACE1 in the literature, which can be used for subsequent research on whether BACE1 is a post-translationally modified drug.
Collapse
Affiliation(s)
- Wen Wen
- Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137. China
| | - Ping Li
- Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137. China
| | - Panwang Liu
- Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137. China
| | - Shijun Xu
- Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137. China
| | - Fushun Wang
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, Sichuan 610000. China
| | - Jason H Huang
- Department of Neurosurgery, Baylor Scott & White Health Science Center, Temple, TX 79409. United States
| |
Collapse
|
|
41
|
Bao H, Liu Y, Zhang M, Chen Z, Zhang W, Ge Y, Kang D, Gao F, Shen Y. Increased β-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment. Alzheimers Dement 2021; 17:1097-1108. [PMID: 33410588 DOI: 10.1002/alz.12276] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Patients with type 2 diabetes mellitus (T2DM) are at a high risk of cognitive impairment, with insulin resistance playing a pivotal role. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is considered a predictor of Alzheimer's disease. However, the potential roles of BACE1 in insulin resistance and the risk of cognitive impairment in T2DM remain unclear. METHODS We measured plasma BACE1 levels, BACE1 cleavage activities for Swedish mutant amyloid precursor protein (APPsw) and insulin receptor β subunit (INSR-β), and soluble INSR (sINSR) levels in a clinical cohort study. RESULTS T2DM patients with or without cognitive impairment exhibited elevated plasma BACE1 levels and BACE1 enzymatic activities for APPsw and INSR-β, and sINSR levels. Moreover, the glycemic status correlated with elevated BACE1 levels and BACE1-mediated INSR cleavage, which was associated with insulin resistance. DISCUSSION The elevated BACE1 levels in T2DM may contribute to increasing the cognitive impairment risk through both amyloidogenesis and insulin resistance.
Collapse
Affiliation(s)
- Hong Bao
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yiming Liu
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengguo Zhang
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zuolong Chen
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Weiwei Zhang
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Yuhao Ge
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Dongmei Kang
- Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Feng Gao
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Yong Shen
- Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.,Institute on Aging and Brain Disorders, First Affiliated Hospital of University of Science and Technology of China, Hefei, China.,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| |
Collapse
|
|
42
|
Jash K, Gondaliya P, Sunkaria A, Kalia K. MicroRNA-29b Modulates β-Secretase Activity in SH-SY5Y Cell Line and Diabetic Mouse Brain. Cell Mol Neurobiol 2020; 40:1367-1381. [PMID: 32198621 PMCID: PMC11448805 DOI: 10.1007/s10571-020-00823-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/29/2020] [Indexed: 01/18/2023]
Abstract
Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes which may lead to Alzheimer's disease (AD) at a later stage. MicroRNAs are a class of non-coding RNAs that are found to play a role in diabetes. Downregulation of microRNA-29b in diabetes is well reported. Moreover, microRNA-29b is also reported to target the 3' UTR of β-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aβ) in AD via cleavage of amyloid precursor protein (APP). Therefore, the present study was designed to elucidate whether microRNA-29b could be a link between diabetes and dementia. In the in vitro and in vivo diabetic model, we found downregulation of microRNA-29b due to hyperglycemia. After human microRNA-29b treatment, there was a significant improvement in the short-term and spatial memory in diabetic mice. Also, the human microRNA-29b treatment decreased oxidative stress and BACE-1 activity in diabetes. The present findings revealed that the downregulation of microRNA-29b in diabetes could be associated with memory impairment and increased BACE-1 activity. These results would give a future direction to study the role played by microRNAs in diabetes-associated memory impairment and hence aid in the development of therapeutics to treat the same.
Collapse
Affiliation(s)
- Kavya Jash
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Piyush Gondaliya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Aditya Sunkaria
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India.
| |
Collapse
|
|
43
|
Mahmood R, Kayani WK, Ahmed T, Malik F, Hussain S, Ashfaq M, Ali H, Rubnawaz S, Green BD, Calderwood D, Kenny O, Rivera GA, Mirza B, Rasheed F. Assessment of antidiabetic potential and phytochemical profiling of Rhazya stricta root extracts. BMC Complement Med Ther 2020; 20:293. [PMID: 32993632 PMCID: PMC7523044 DOI: 10.1186/s12906-020-03035-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 07/24/2020] [Indexed: 12/17/2022] Open
Abstract
Background Diabetes mellitus is a chronic disease characterized by hyperglycemia that may occur due to genetic, environmental or lifestyle factors. Natural remedies have been used to treat diabetes since long and many antidiabetic compounds of varied efficacies have been isolated from medicinal plants. Rhazya stricta has been used for decades for the treatment of diabetes mellitus and associated ailments. Considering the folkloric use of R. stricta against diabetes, it was aimed to investigate the effectiveness of its root extracts against diabetes through in vitro assays and in vivo studies using animal model along with phytochemical profiling through GCMS. Methods Various fractions of Rhazya stricta obtained through column chromatography were evaluated for a variety of assays including α-glucosidase, Dipeptidyl peptidase-IV (DPP-IV), β-secretase and Glucagon-like peptide-1 (GLP-1) secretion studies. For the in vivo studies the alloxan-induced diabetic mice were treated with root extracts and blood glucose levels, HbA1C, and other biochemical markers along with the histological study of the liver were done. The phytochemical identification was performed using an Agilent 7890B GC coupled to a 7010 Triple Quadrupole (MS/MS) system. GraphPad Prism software version 5.01 was used for statistical analysis. Results Majority of the extract fractions showed excellent results against diabetes by inhibiting enzymes DPP-IV (Up to 61%) and β-secretase (Up to 83%) with IC50s 979 μg/ml and 169 μg/ml respectively with increase in the GLP1 secretion. The results of in vivo studies indicated a marked reduction in blood glucose and HbA1c levels along with positive effects on other parameters like lipid profile, liver functions and renal functions of extract-treated mice as compared to control. The histological examination of the liver demonstrated hepatoprotective effects against diabetes led changes and various classes of phytochemicals were also identified through GCMS in different fractions. Conclusion The results revealed strong antidiabetic activity of R. stricta root with the potential to protect body organs against diabetic changes. Moreover, a variety of phytochemicals has also been identified through GCMS that might be responsible for the antidiabetic potential of Rhazya stricta root. Graphical abstract ![]()
Collapse
Affiliation(s)
- Rashid Mahmood
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Waqas Khan Kayani
- Department of Plant Breeding, Swedish University of Agricultural Sciences, Växtskyddsvägen 1, SE-230 53 Alnarp, Uppsala, Sweden
| | - Tanveer Ahmed
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Farnaz Malik
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Shahzad Hussain
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Muhammad Ashfaq
- Drugs Control & Traditional Medicines Division, National Institute of Health, Islamabad, Pakistan
| | - Hussain Ali
- Animal House, National Institute of Health, Islamabad, Pakistan
| | - Samina Rubnawaz
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Brian D Green
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Danielle Calderwood
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Owen Kenny
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Gerardo A Rivera
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland
| | - Bushra Mirza
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Faiza Rasheed
- KTH Royal Institute of Technology, School of Chemical Science and Engineering, SE-100 44, Stockholm, Sweden.
| |
Collapse
|
|
44
|
Yazdani M, Edraki N, Badri R, Khoshneviszadeh M, Iraji A, Firuzi O. 5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer's disease modifying agents. Mol Divers 2020; 24:641-654. [PMID: 31327094 DOI: 10.1007/s11030-019-09970-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/05/2019] [Indexed: 10/26/2022]
Abstract
In this study, new derivatives of 5,6-diphenyl triazine-thio methyl triazole hybrid were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease. Among all synthesized compounds, 4a and 4h showed the best inhibitory activities against BACE1 (40% and 37.5% μM inhibition at 50 µM, respectively). Molecular docking studies showed that compound 4a occupied the entire BACE1 enzyme and the thio triazine fragment deeply penetrates into S2 binding site via two hydrogen bonds with Thr72 and Gln73 amino acids. Different aromatic moieties occupy S'2 pocket via hydrophobic interactions. 6-Phenyl ring also had a potential hydrophobic interaction with S1 pocket. In vitro ChE inhibitory assay demonstrated that most of the derivatives exhibited more selectivity toward BuChE than AChE. 4c as the most potent BuChE inhibitor displayed an IC50 value of 6.4 µM, and 4b exhibited AChE inhibitory activity with 25.1% inhibition at 50 μM. Further, molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket. Moreover, molecular docking study of 4a, 4b and 4c with ChE active site was also performed.
Collapse
Affiliation(s)
- Mahnaz Yazdani
- Department of Chemistry, Khozestan Science and Research Branch, Islamic Azad University, Ahvaz, Iran
- Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
| | - Najmeh Edraki
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Rashid Badri
- Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran
| | - Mehdi Khoshneviszadeh
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Aida Iraji
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
45
|
Mate A, Blanca AJ, Salsoso R, Toledo F, Stiefel P, Sobrevia L, Vázquez CM. Insulin Therapy in Pregnancy Hypertensive Diseases and its Effect on the Offspring and Mother Later in Life. Curr Vasc Pharmacol 2020; 17:455-464. [PMID: 30426902 DOI: 10.2174/1570161117666181114125109] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 10/07/2018] [Accepted: 10/10/2018] [Indexed: 01/24/2023]
Abstract
Pregnancy hypertensive disorders such as Preeclampsia (PE) are strongly correlated with insulin resistance, a condition in which the metabolic handling of D-glucose is deficient. In addition, the impact of preeclampsia is enhanced by other insulin-resistant disorders, including polycystic ovary syndrome and obesity. For this reason, there is a clear association between maternal insulin resistance, polycystic ovary syndrome, obesity and the development of PE. However, whether PE is a consequence or the cause of these disorders is still unclear. Insulin therapy is usually recommended to pregnant women with diabetes mellitus when dietary and lifestyle measures have failed. The advantage of insulin therapy for Gestational Diabetes Mellitus (GDM) patients with hypertension is still controversial; surprisingly, there are no studies in which insulin therapy has been used in patients with hypertension in pregnancy without or with an established GDM. This review is focused on the use of insulin therapy in hypertensive disorders in the pregnancy and its effect on offspring and mother later in life. PubMed and relevant medical databases have been screened for literature covering research in the field especially in the last 5-10 years.
Collapse
Affiliation(s)
- Alfonso Mate
- Departamento de Fisiologia, Facultad de Farmacia, Universidad de Sevilla, E-41012 Sevilla, Spain.,Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/ Universidad de Sevilla, E- 41013 Sevilla, Spain
| | - Antonio J Blanca
- Departamento de Fisiologia, Facultad de Farmacia, Universidad de Sevilla, E-41012 Sevilla, Spain
| | - Rocío Salsoso
- Departamento de Fisiologia, Facultad de Farmacia, Universidad de Sevilla, E-41012 Sevilla, Spain.,Unidad de Enfermedades Coronarias Agudas, Instituto del Corazón, Escuela de Medicina, Universidad de Sao Paulo, Sao Paulo 05403-000 Brazil
| | - Fernando Toledo
- Department of Basic Sciences, Faculty of Sciences, Universidad del Bío-Bío, Chillan 3780000, Chile.,Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago 8330024, Chile
| | - Pablo Stiefel
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/ Universidad de Sevilla, E- 41013 Sevilla, Spain
| | - Luis Sobrevia
- Departamento de Fisiologia, Facultad de Farmacia, Universidad de Sevilla, E-41012 Sevilla, Spain.,Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago 8330024, Chile.,University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia
| | - Carmen M Vázquez
- Departamento de Fisiologia, Facultad de Farmacia, Universidad de Sevilla, E-41012 Sevilla, Spain.,Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/ Universidad de Sevilla, E- 41013 Sevilla, Spain
| |
Collapse
|
|
46
|
Jash K, Gondaliya P, Kirave P, Kulkarni B, Sunkaria A, Kalia K. Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease. Drug Dev Res 2020; 81:144-164. [DOI: 10.1002/ddr.21579] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/12/2019] [Accepted: 06/30/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Kavya Jash
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| | - Piyush Gondaliya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| | - Prathibha Kirave
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| | - Bhagyashri Kulkarni
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| | - Aditya Sunkaria
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| | - Kiran Kalia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Ahmedabad Gandhinagar Gujarat India
| |
Collapse
|
|
47
|
Mphahlele MJ, Choong YS, Maluleka MM, Gildenhuys S. Synthesis, In Vitro Evaluation and Molecular Docking of the 5-Acetyl-2-aryl-6-hydroxybenzo[ b]furans against Multiple Targets Linked to Type 2 Diabetes. Biomolecules 2020; 10:E418. [PMID: 32156083 PMCID: PMC7175131 DOI: 10.3390/biom10030418] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/12/2020] [Accepted: 02/19/2020] [Indexed: 02/06/2023] Open
Abstract
The 5-acetyl-2-aryl-6-hydroxybenzo[b]furans 2a-h have been evaluated through in vitro enzymatic assay against targets which are linked to type 2 diabetes (T2D), namely, α-glucosidase, protein tyrosine phosphatase 1B (PTP1B) and β-secretase. These compounds have also been evaluated for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging method. The most active compounds against α-glucosidase and/or PTP1B, namely, 4-fluorophenyl 2c, 4-methoxyphenyl 2g and 3,5-dimethoxyphenyl substituted 2h derivatives were also evaluated for potential anti-inflammatory properties against cyclooxygenase-2 activity. The Lineweaver-Burk and Dixon plots were used to determine the type of inhibition on compounds 2c and 2h against α-glucosidase and PTP1B receptors. The interactions were investigated in modelled complexes against α-glucosidase and PTP1B via molecular docking.
Collapse
Affiliation(s)
- Malose J. Mphahlele
- Department of Chemistry, University of South Africa, Private Bag X06, Florida 1710, South Africa
| | - Yee Siew Choong
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia;
| | - Marole M. Maluleka
- Department of Chemistry, University of South Africa, Private Bag X06, Florida 1710, South Africa
| | - Samantha Gildenhuys
- Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa;
| |
Collapse
|
|
48
|
Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance. Sci Rep 2020; 10:1725. [PMID: 32015418 PMCID: PMC6997356 DOI: 10.1038/s41598-020-58361-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 01/13/2020] [Indexed: 12/30/2022] Open
Abstract
Recent evidence suggests that enhanced protease-mediated inflammation may promote insulin resistance and result in diabetes. This study tested the hypothesis that serine protease plays a pivotal role in type 2 diabetes, and inhibition of serine protease activity prevents hyperglycemia in diabetic animals by modulating insulin signaling pathway. We conducted a single-center, cross-sectional study with 30 healthy controls and 57 patients with type 2 diabetes to compare plasma protease activities and inflammation marker between groups. Correlations of plasma total and serine protease activities with variables were calculated. In an in-vivo study, LDLR−/− mice were divided into normal chow diet, high-fat diet (HFD), and HFD with selective serine protease inhibition groups to examine the differences of obesity, blood glucose level, insulin resistance and serine protease activity among groups. Compared with controls, diabetic patients had significantly increased plasma total protease, serine protease activities, and also elevated inflammatory cytokines. Plasma serine protease activity was positively correlated with body mass index, hemoglobin A1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-α, and negatively with adiponectin concentration. In the animal study, administration of HFD progressively increased body weight, fasting glucose level, HOMA-IR, and upregulated serine protease activity. Furthermore, in-vivo serine protease inhibition significantly suppressed systemic inflammation, reduced fasting glucose level, and improved insulin resistance, and these effects probably mediated by modulating insulin receptor and cytokine expression in visceral adipose tissue. Our findings support the serine protease may play an important role in type 2 diabetes and suggest a rationale for a therapeutic strategy targeting serine protease for clinical prevention of type 2 diabetes.
Collapse
|
|
49
|
Dekeryte R, Hull C, Plucińska K, Khan S, Kamli-Salino S, Mody N, Morrice N, McLaughlin C, Gault V, Platt B, Delibegovic M. Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice. Biochem Pharmacol 2019; 166:222-230. [PMID: 31103416 DOI: 10.1016/j.bcp.2019.05.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/14/2019] [Indexed: 01/21/2023]
|
|
50
|
Yaghoobi H, Azizi H, Banitalebi-Dehkordi M, Mohammad Rezaei F, Arsang-Jnag S, Taheri M, Ghafouri-Fard S. Beta-Secretase 1 ( BACE1) Is Down-Regulated in Invasive Ductal Carcinoma of Breast. Rep Biochem Mol Biol 2019; 8:200-207. [PMID: 31832446 PMCID: PMC6844613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 08/15/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND The enzyme beta-secretase 1 (BACE1) and its antisense transcript (BACE1-AS) have been implicated in the pathogenesis of Alzheimer's disease. Moreover, several lines of evidence point to their contribution in tumorigenesis. METHODS In the present study, we evaluated expression of BACE1 mRNA (BACE1) and BACE1-AS in 54 breast cancer tissues and 54 adjacent non-cancerous tissues (ANCTs) from the same patients using quantitative real-time PCR. RESULTS BACE1 was significantly down-regulated in tumoral tissues compared with ANCTs, while BACE1- AS expression was not significantly different between tumoral tissues and ANCTs. The Bayesian Multilevel model showed a significant difference in BACE1 expression between stage 1 and 2 cancers after age-effect adjustments. BACE1-AS expression was significantly greater in ER-positive than in ER-negative samples (P=0.01). BACE1 and BACE1-AS expression were not correlated with patient ages in any sample sets. CONCLUSION Significant correlations were detected between expression of these genes in both tumoral tissues and ANCTs. The current study provides evidence for differential BACE1 expression in breast tissues and suggests further assessment of the role of BACE1 in the pathogenesis of cancer.
Collapse
Affiliation(s)
- Hajar Yaghoobi
- University of Medical Sciences, Shahrekord, Iran.
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Hakim Azizi
- Department of Medical Parasitology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
| | | | - Fatemeh Mohammad Rezaei
- Department of Medical Genetic, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Shahram Arsang-Jnag
- Clinical Research Development Center (CRDU), Qom University of Medical Sciences, Qom, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|