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1
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Song H, Lee J, Lee Y, Kim S, Kang S. Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer's Disease with Therapeutic Implications. Int J Mol Sci 2025; 26:3272. [PMID: 40244088 PMCID: PMC11989502 DOI: 10.3390/ijms26073272] [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: 02/13/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Chronic alcohol consumption leads to excessive production of reactive oxygen species (ROS), driving oxidative stress that contributes to both alcohol use disorder (AUD) and Alzheimer's disease (AD). This review explores how ROS-mediated mitochondrial dysfunction and neuroinflammation serve as shared pathological mechanisms linking these conditions. We highlight the role of alcohol-induced oxidative damage in exacerbating neurodegeneration and compare ROS-related pathways in AUD and AD. Finally, we discuss emerging therapeutic strategies, including mitochondrial antioxidants and inflammasome inhibitors, that target oxidative stress to mitigate neurodegeneration. Understanding these overlapping mechanisms may provide new insights for preventing and treating ROS-driven neurodegenerative disorders.
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Affiliation(s)
| | | | | | | | - Shinwoo Kang
- Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, 31, Soonchunhyang 6-gil, Dongnam-gu, Cheonan-si 31151, Chungcheongnam-do, Republic of Korea; (H.S.); (J.L.); (Y.L.); (S.K.)
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2
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Granov R, Vedad S, Wang SH, Durham A, Shah D, Pasinetti GM. The Role of the Neural Exposome as a Novel Strategy to Identify and Mitigate Health Inequities in Alzheimer's Disease and Related Dementias. Mol Neurobiol 2025; 62:1205-1224. [PMID: 38967905 PMCID: PMC11711138 DOI: 10.1007/s12035-024-04339-6] [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: 12/26/2023] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
With the continuous increase of the elderly population, there is an urgency to understand and develop relevant treatments for Alzheimer's disease and related dementias (ADRD). In tandem with this, the prevalence of health inequities continues to rise as disadvantaged communities fail to be included in mainstream research. The neural exposome poses as a relevant mechanistic approach and tool for investigating ADRD onset, progression, and pathology as it accounts for several different factors: exogenous, endogenous, and behavioral. Consequently, through the neural exposome, health inequities can be addressed in ADRD research. In this paper, we address how the neural exposome relates to ADRD by contributing to the discourse through defining how the neural exposome can be developed as a tool in accordance with machine learning. Through this, machine learning can allow for developing a greater insight into the application of transferring and making sense of experimental mouse models exposed to health inequities and potentially relate it to humans. The overall goal moving beyond this paper is to define a multitude of potential factors that can increase the risk of ADRD onset and integrate them to create an interdisciplinary approach to the study of ADRD and subsequently translate the findings to clinical research.
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Affiliation(s)
- Ravid Granov
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA
| | - Skyler Vedad
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA
| | - Shu-Han Wang
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA
| | - Andrea Durham
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA
| | - Divyash Shah
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA
| | - Giulio Maria Pasinetti
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10019, USA.
- Geriatrics Research, Education and Clinical Center, JJ Peters VA Medical Center, Bronx, NY, 10468, USA.
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3
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Dow LF, Pathirage R, Erickson HE, Amani E, Ronning DR, Trippier PC. Synthesis and biological characterization of a 17β hydroxysteroid dehydrogenase type 10 (17β-HSD10) inhibitor. RSC Med Chem 2024:d4md00733f. [PMID: 39618963 PMCID: PMC11605429 DOI: 10.1039/d4md00733f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/12/2024] [Indexed: 12/12/2024] Open
Abstract
Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.
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Affiliation(s)
- Louise F Dow
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
| | - Rasangi Pathirage
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
| | - Helen E Erickson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
| | - Edrees Amani
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
| | - Donald R Ronning
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center Omaha Nebraska 68198 USA
- UNMC Center for Drug Design and Innovation, University of Nebraska Medical Center Omaha Nebraska 68198 USA
| | - Paul C Trippier
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center Omaha Nebraska 68198 USA
- UNMC Center for Drug Design and Innovation, University of Nebraska Medical Center Omaha Nebraska 68198 USA
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4
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Kale MB, Bhondge HM, Wankhede NL, Shende PV, Thanekaer RP, Aglawe MM, Rahangdale SR, Taksande BG, Pandit SB, Upaganlawar AB, Umekar MJ, Kopalli SR, Koppula S. Navigating the intersection: Diabetes and Alzheimer's intertwined relationship. Ageing Res Rev 2024; 100:102415. [PMID: 39002642 DOI: 10.1016/j.arr.2024.102415] [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: 06/14/2024] [Revised: 07/06/2024] [Accepted: 07/06/2024] [Indexed: 07/15/2024]
Abstract
Alzheimer's disease (AD) and Diabetes mellitus (DM) exhibit comparable pathophysiological pathways. Genetic abnormalities in APP, PS-1, and PS-2 are linked to AD, with diagnostic aid from CSF and blood biomarkers. Insulin dysfunction, termed "type 3 diabetes mellitus" in AD, involves altered insulin signalling and neuronal shrinkage. Insulin influences beta-amyloid metabolism, exacerbating neurotoxicity in AD and amyloid production in DM. Both disorders display impaired glucose transporter expression, hastening cognitive decline. Mitochondrial dysfunction and Toll-like receptor 4-mediated inflammation worsen neurodegeneration in both diseases. ApoE4 raises disease risk, especially when coupled with dyslipidemia common in DM. Targeting shared pathways like insulin-degrading enzyme activation and HSP60 holds promise for therapeutic intervention. Recognizing these interconnected mechanisms underscores the imperative for developing tailored treatments addressing the overlapping pathophysiology of AD and DM, offering potential avenues for more effective management of both conditions.
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Affiliation(s)
- Mayur B Kale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | | | - Nitu L Wankhede
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Prajwali V Shende
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Rushikesh P Thanekaer
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Manish M Aglawe
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Sandip R Rahangdale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Brijesh G Taksande
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Sunil B Pandit
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
| | - Aman B Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
| | - Milind J Umekar
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra 441002, India
| | - Spandana Rajendra Kopalli
- Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul 05006, Republic of Korea
| | - Sushruta Koppula
- College of Biomedical and Health Sciences, Konkuk University, Chungju-Si, Chungcheongbuk Do 27478, Republic of Korea.
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5
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Ye Z, Liu Y, Jin X, Wu Y, Zhao H, Gao T, Deng Q, Cheng J, Lin J, Tong Z. Aβ-binding with alcohol dehydrogenase drives Alzheimer's disease pathogenesis: A review. Int J Biol Macromol 2024; 264:130580. [PMID: 38432266 DOI: 10.1016/j.ijbiomac.2024.130580] [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: 02/17/2024] [Accepted: 02/29/2024] [Indexed: 03/05/2024]
Abstract
Although Alzheimer's disease (AD) characterized with senile plaques and neurofibrillary tangles has been found for over 100 years, its molecular mechanisms are ambiguous. More worsely, the developed medicines targeting amyloid-beta (Aβ) and/or tau hyperphosphorylation did not approach the clinical expectations in patients with moderate or severe AD until now. This review unveils the role of a vicious cycle between Aβ-derived formaldehyde (FA) and FA-induced Aβ aggregation in the onset course of AD. Document evidence has shown that Aβ can bind with alcohol dehydrogenase (ADH) to form the complex of Aβ/ADH (ABAD) and result in the generation of reactive oxygen species (ROS) and aldehydes including malondialdehyde, hydroxynonenal and FA; in turn, ROS-derived H2O2 and FA promotes Aβ self-aggregation; subsequently, this vicious cycle accelerates neuron death and AD occurrence. Especially, FA can directly induce neuron death by stimulating ROS generation and tau hyper hyperphosphorylation, and impair memory by inhibiting NMDA-receptor. Recently, some new therapeutical methods including inhibition of ABAD activity by small molecules/synthetic polypeptides, degradation of FA by phototherapy or FA scavengers, have been developed and achieved positive effects in AD transgenic models. Thus, breaking the vicious loop may be promising interventions for halting AD progression.
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Affiliation(s)
- Zuting Ye
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yanming Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xingjiang Jin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiqing Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hang Zhao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tingting Gao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiangfeng Deng
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianhua Cheng
- Department of neurology, the first affiliated hospital of Wenzhou medical University, Wenzhou 325035. China
| | - Jing Lin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Zhiqian Tong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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6
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Gu X, Qi L, Qi Q, Zhou J, Chen S, Wang L. Monoclonal antibody therapy for Alzheimer's disease focusing on intracerebral targets. Biosci Trends 2024; 18:49-65. [PMID: 38382942 DOI: 10.5582/bst.2023.01288] [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] [Indexed: 02/23/2024]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Due to the complexity of the disorder and the presence of the blood-brain barrier (BBB), its drug discovery and development are facing enormous challenges, especially after several failures of monoclonal antibody (mAb) trials. Nevertheless, the Food and Drug Administration's approval of the mAb aducanumab has ushered in a new day. As we better understand the disease's pathogenesis and identify novel intracerebral therapeutic targets, antibody-based therapies have advanced over the past few years. The mAb drugs targeting β-amyloid or hyperphosphorylated tau protein are the focus of the current research. Massive neuronal loss and glial cell-mediated inflammation are also the vital pathological hallmarks of AD, signaling a new direction for research on mAb drugs. We have elucidated the mechanisms by which AD-specific mAbs cross the BBB to bind to targets. In order to investigate therapeutic approaches to treat AD, this review focuses on the promising mAbs targeting intracerebral dysfunction and related strategies to cross the BBB.
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Affiliation(s)
- Xiaolei Gu
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Long Qi
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
| | - Qing Qi
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Jing Zhou
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Song Chen
- Postdoctoral Station of Xiamen University, Fujian, China
| | - Ling Wang
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
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7
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Sousa T, Moreira PI, Cardoso S. Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease. Biomedicines 2023; 11:2331. [PMID: 37760774 PMCID: PMC10525414 DOI: 10.3390/biomedicines11092331] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alzheimer's disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD's cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria's health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.
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Affiliation(s)
- Tiago Sousa
- Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal;
| | - Paula I. Moreira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal
| | - Susana Cardoso
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
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8
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Jekabsone A, Jankeviciute S, Pampuscenko K, Borutaite V, Morkuniene R. The Role of Intracellular Ca 2+ and Mitochondrial ROS in Small Aβ 1-42 Oligomer-Induced Microglial Death. Int J Mol Sci 2023; 24:12315. [PMID: 37569690 PMCID: PMC10418347 DOI: 10.3390/ijms241512315] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/27/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ1-42 structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ1-42 species-small oligomers, large oligomers, insoluble fibrils, and monomers-were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ1-42 oligomers induced a concentration- and time-dependent increase in intracellular Ca2+ and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca2+ nor viability was significantly affected by larger Aβ1-42 species or monomers. In addition, the small Aβ1-42 oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ1-42-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.
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Affiliation(s)
- Aiste Jekabsone
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania; (A.J.); (S.J.); (K.P.); (V.B.)
- Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania
| | - Silvija Jankeviciute
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania; (A.J.); (S.J.); (K.P.); (V.B.)
| | - Katryna Pampuscenko
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania; (A.J.); (S.J.); (K.P.); (V.B.)
| | - Vilmante Borutaite
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania; (A.J.); (S.J.); (K.P.); (V.B.)
| | - Ramune Morkuniene
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania; (A.J.); (S.J.); (K.P.); (V.B.)
- Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania
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9
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Wilkins HM. Interactions between amyloid, amyloid precursor protein, and mitochondria. Biochem Soc Trans 2023; 51:173-182. [PMID: 36688439 PMCID: PMC9987971 DOI: 10.1042/bst20220518] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.
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Affiliation(s)
- Heather M. Wilkins
- University of Kansas Alzheimer's Disease Center, Kansas City, KS, U.S.A
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, U.S.A
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, U.S.A
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10
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Rahman MM, Tumpa MAA, Rahaman MS, Islam F, Sutradhar PR, Ahmed M, Alghamdi BS, Hafeez A, Alexiou A, Perveen A, Ashraf GM. Emerging Promise of Therapeutic Approaches Targeting Mitochondria in Neurodegenerative Disorders. Curr Neuropharmacol 2023; 21:1081-1099. [PMID: 36927428 PMCID: PMC10286587 DOI: 10.2174/1570159x21666230316150559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 03/18/2023] Open
Abstract
Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.
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Affiliation(s)
- Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Mst. Afroza Alam Tumpa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Md. Saidur Rahaman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Popy Rani Sutradhar
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Muniruddin Ahmed
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- The Neuroscience Research Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdul Hafeez
- Glocal School of Pharmacy, Glocal University, Mirzapur Pole, Saharanpur, Uttar Pradesh, India
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Wien, Austria
| | - Asma Perveen
- Glocal School of Life Sciences, Glocal University, Mirzapur Pole, Saharanpur, Uttar Pradesh, India
| | - Ghulam Md. Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
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11
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Pandey SN, Singh G, Semwal BC, Gupta G, Alharbi KS, Almalki WH, Albratty M, Najmi A, Meraya AM. Therapeutic approaches of nutraceuticals in the prevention of Alzheimer's disease. J Food Biochem 2022; 46:e14426. [PMID: 36169224 DOI: 10.1111/jfbc.14426] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 01/13/2023]
Abstract
Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti-Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti-inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high-quality clinical trials. Given the potential of nutraceuticals to battle AD as multi-targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors 'knowledge, modification of blood-brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. PRACTICAL APPLICATIONS: Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost-effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease.
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Affiliation(s)
- Surya Nath Pandey
- Department of Pharmacology, University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India.,Department of Pharmacology, College of Pharmacy, Teerthanker Mahaveer University, Moradabad, UP, India
| | - Gurfateh Singh
- Department of Pharmacology, University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India
| | - Bhupesh Chander Semwal
- Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jaipur, India.,Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.,Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Asim Najmi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Abdulkarim M Meraya
- Pharmacy Practice Research Unit, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
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12
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Neuroprotective Effects of the Psychoactive Compound Biatractylolide (BD) in Alzheimer's Disease. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238294. [PMID: 36500385 PMCID: PMC9737891 DOI: 10.3390/molecules27238294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria play a central role in the survival or death of neuronal cells, and they are regulators of energy metabolism and cell death pathways. Many studies support the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Biatractylolide (BD) is a kind of internal symmetry double sesquiterpene novel ester compound isolated from the Chinese medicinal plant Baizhu, has neuroprotective effects in Alzheimer's disease. We developed a systematic pharmacological model based on chemical pharmacokinetic and pharmacological data to identify potential compounds and targets of Baizhu. The neuroprotective effects of BD in PC12 (rat adrenal pheochromocytoma cells) and SH-SY5Y (human bone marrow neuroblastoma cells) were evaluated by in vitro experiments. Based on the predicted results, we selected 18 active compounds, which were associated with 20 potential targets and 22 signaling pathways. Compound-target, target-disease and target-pathway networks were constructed using Cytoscape 3.2.1. And verified by in vitro experiments that BD could inhibit Aβ by reducing oxidative stress and decreasing CytC release induced mPTP opening. This study provides a theoretical basis for the development of BD as an anti-Alzheimer's disease drug.
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13
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Dewanjee S, Chakraborty P, Bhattacharya H, Chacko L, Singh B, Chaudhary A, Javvaji K, Pradhan SR, Vallamkondu J, Dey A, Kalra RS, Jha NK, Jha SK, Reddy PH, Kandimalla R. Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress. Free Radic Biol Med 2022; 193:134-157. [PMID: 36206930 DOI: 10.1016/j.freeradbiomed.2022.09.032] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/16/2022] [Accepted: 09/29/2022] [Indexed: 12/06/2022]
Abstract
Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.
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Affiliation(s)
- Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Pratik Chakraborty
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Hiranmoy Bhattacharya
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700 032, West Bengal, India
| | - Leena Chacko
- BioAnalytical Lab, Meso Scale Discovery, 1601 Research Blvd, Rockville, MD, USA
| | - Birbal Singh
- ICAR-Indian Veterinary Research Institute (IVRI), Regional Station, Palampur, 176061, Himachal Pradesh, India
| | - Anupama Chaudhary
- Orinin-BioSystems, LE-52, Lotus Road 4, CHD City, Karnal, 132001, Haryana, India
| | - Kalpana Javvaji
- CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India
| | | | | | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, 700073, India
| | - Rajkumar Singh Kalra
- Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 9040495, Japan
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, UP, 201310, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, UP, 201310, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
| | - P Hemachandra Reddy
- Internal Medicine Department, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology Departments School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Ramesh Kandimalla
- CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, India; Department of Biochemistry, Kakatiya Medical College, Warangal, India.
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14
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Fišar Z. Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets. Biomolecules 2022; 12:1676. [PMID: 36421690 PMCID: PMC9687482 DOI: 10.3390/biom12111676] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/23/2022] [Accepted: 11/09/2022] [Indexed: 08/27/2023] Open
Abstract
Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.
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Affiliation(s)
- Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague, Czech Republic
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15
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Is the Brain Undernourished in Alzheimer's Disease? Nutrients 2022; 14:nu14091872. [PMID: 35565839 PMCID: PMC9102563 DOI: 10.3390/nu14091872] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 01/27/2023] Open
Abstract
Cerebrospinal fluid (CSF) amino acid (AA) levels and CSF/plasma AA ratios in Alzheimer Disease (AD) in relation to nutritional state are not known. Methods: In 30 fasting patients with AD (46% males, 74.4 ± 8.2 years; 3.4 ± 3.2 years from diagnosis) and nine control (CTRL) matched subjects, CSF and venous blood samples were drawn for AA measurements. Patients were stratified according to nutritional state (Mini Nutritional Assessment, MNA, scores). Results: Total CSF/plasma AA ratios were lower in the AD subpopulations than in NON-AD (p < 0.003 to 0.017. In combined malnourished (16.7%; MNA < 17) and at risk for malnutrition (36.6%, MNA 17−24) groups (CG), compared to CTRL, all essential amino acids (EAAs) and 30% of non-EAAs were lower (p < 0.018 to 0.0001), whereas in normo-nourished ADs (46.7%, MNA > 24) the CSF levels of 10% of EAAs and 25% of NON-EAAs were decreased (p < 0.05 to 0.00021). CG compared to normo-nourished ADs, had lower CSF aspartic acid, glutamic acid and Branched-Chain AA levels (all, p < 0.05 to 0.003). CSF/plasma AA ratios were <1 in NON-AD but even lower in the AD population. Conclusions: Compared to CTRL, ADs had decreased CSF AA Levels and CSF/plasma AA ratios, the degree of which depended on nutritional state.
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16
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Podsiedlik M, Markowicz-Piasecka M, Sikora J. The Influence of Selected Antipsychotic Drugs on Biochemical Aspects of Alzheimer's Disease. Int J Mol Sci 2022; 23:4621. [PMID: 35563011 PMCID: PMC9102502 DOI: 10.3390/ijms23094621] [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: 03/12/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 01/27/2023] Open
Abstract
The aim of this study was to assess the potency of selected antipsychotic drugs (haloperidol (HAL), bromperidol (BRMP), benperidol (BNP), penfluridol (PNF), pimozide (PIM), quetiapine (QUET) and promazine (PROM)) on the main pathological hallmarks of Alzheimer's disease (AD). Binary mixtures of donepezil and antipsychotics produce an anti-BuChE effect, which was greater than either compound alone. The combination of rivastigmine and antipsychotic drugs (apart from PNF) enhanced AChE inhibition. The tested antipsychotics (excluding HAL and PNF) significantly reduce the early stage of Aβ aggregation. BRMP, PIM, QUET and PROM were found to substantially inhibit Aβ aggregation after a longer incubation time. A test of human erythrocytes hemolysis showed that short-term incubation of red blood cells (RBCs) with QUET resulted in decreased hemolysis. The antioxidative properties of antipsychotics were also proved in human umbilical vein endothelial cells (HUVEC); all tested drugs were found to significantly increase cell viability. In the case of astrocytes, BNP, PNF, PIM and PROM showed antioxidant potential.
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Affiliation(s)
- Maria Podsiedlik
- Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
| | - Magdalena Markowicz-Piasecka
- Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
| | - Joanna Sikora
- Department of Bioinorganic Chemistry, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
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17
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Mishra A, Wang Y, Yin F, Vitali F, Rodgers KE, Soto M, Mosconi L, Wang T, Brinton RD. A tale of two systems: Lessons learned from female mid-life aging with implications for Alzheimer's prevention & treatment. Ageing Res Rev 2022; 74:101542. [PMID: 34929348 PMCID: PMC8884386 DOI: 10.1016/j.arr.2021.101542] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 12/05/2021] [Accepted: 12/13/2021] [Indexed: 02/03/2023]
Abstract
Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.
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Affiliation(s)
- Aarti Mishra
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Yiwei Wang
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Fei Yin
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Francesca Vitali
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Kathleen E Rodgers
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Maira Soto
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Lisa Mosconi
- Department of Neurology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Tian Wang
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA
| | - Roberta D Brinton
- Center for Innovation in Brain Science, University of Arizona, Tucson, AZ 85719, USA.
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18
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Zhou Z, Bai J, Zhong S, Zhang R, Kang K, Zhang X, Xu Y, Zhao C, Zhao M. Downregulation of PIK3CB Involved in Alzheimer's Disease via Apoptosis, Axon Guidance, and FoxO Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1260161. [PMID: 35096262 PMCID: PMC8794666 DOI: 10.1155/2022/1260161] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 01/08/2022] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the molecular function of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) underlying Alzheimer's disease (AD). METHODS RNA sequencing data were used to filtrate differentially expressed genes (DEGs) in AD/nondementia control and PIK3CB-low/high groups. An unbiased coexpression network was established to evaluate module-trait relationships by using weight gene correlation network analysis (WGCNA). Global regulatory network was constructed to predict the protein-protein interaction. Further cross-talking pathways of PIK3CB were identified by functional enrichment analysis. RESULTS The mean expression of PIK3CB in AD patients was significantly lower than those in nondementia controls. We identified 2,385 DEGs from 16,790 background genes in AD/control and PIK3CB-low/high groups. Five coexpression modules were established using WGCNA, which participated in apoptosis, axon guidance, long-term potentiation (LTP), regulation of actin cytoskeleton, synaptic vesicle cycle, FoxO, mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) signaling pathways. DEGs with strong relation to AD and low PIK3CB expression were extracted to construct a global regulatory network, in which cross-talking pathways of PIK3CB were identified, such as apoptosis, axon guidance, and FoxO signaling pathway. The occurrence of AD could be accurately predicted by low PIK3CB based on the area under the curve of 71.7%. CONCLUSIONS These findings highlight downregulated PIK3CB as a potential causative factor of AD, possibly mediated via apoptosis, axon guidance, and FoxO signaling pathway.
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Affiliation(s)
- Zhike Zhou
- Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Jun Bai
- Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, 130033 Jilin, China
| | - Shanshan Zhong
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Rongwei Zhang
- Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Kexin Kang
- Department of Geriatrics, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Xiaoqian Zhang
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Ying Xu
- Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, 130033 Jilin, China
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, The University of Georgia, USA
| | - Chuansheng Zhao
- Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China
| | - Mei Zhao
- Department of Cardiology, The Shengjing Affiliated Hospital, China Medical University, Shenyang, 110004 Liaoning, China
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19
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Wang Q, Lu M, Zhu X, Gu X, Zhang T, Xia C, Yang L, Xu Y, Zhou M. Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer’s Disease in Later Life. Aging Dis 2022; 13:1127-1145. [PMID: 35855329 PMCID: PMC9286915 DOI: 10.14336/ad.2022.0221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/21/2022] [Indexed: 11/01/2022] Open
Affiliation(s)
- Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengna Lu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyu Zhu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinyi Gu
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Zhang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Xia
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Li Yang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Xu
- Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Correspondence should be addressed to: Dr. Mingmei Zhou, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. E-mail:
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20
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Chung JY, Kim OY, Song J. Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter. Nutr Rev 2021; 80:774-785. [PMID: 34957519 PMCID: PMC8907488 DOI: 10.1093/nutrit/nuab118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abstract
Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.
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Affiliation(s)
- Ji Yeon Chung
- Department of Neurology, Chosun University Medical School, Gwangju, Republic of Korea
| | - Oh Yoen Kim
- Department of Food Science and Nutrition and the Department of Health Sciences, Dong-A University, Busan, Republic of Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, Republic of Korea
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21
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Arora A, Behl T, Sehgal A, Singh S, Sharma N, Mathew B, Bungau S. Targeting cellular batteries for the therapy of neurological diseases. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:41517-41532. [PMID: 34080116 DOI: 10.1007/s11356-021-14665-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 05/27/2021] [Indexed: 06/12/2023]
Abstract
The mitochondria, apart from being known as the cell's "powerhouse," are crucial in the viability of nerve cells. Any damage to these cellular organelles can result in their cellular level dysfunction which includes rapidly multiplying reactive oxygen species (ROS) from the mitochondrial membrane, impaired calcium ion homeostasis, and disturbed mitochondrial dynamics by the formation of permeability transition pore in mitochondria. All these impaired biochemical changes lead to various neurological disorders such as progressive supranuclear palsy (PSP), Parkinson's disease (PD), and Alzheimer's disease (AD). Moreover, impaired mitochondrial functions are particularly prone to damage owing to prolonged lifespan and stretched length of the neurons. At the same time, neurons are highly dependent on ATP, and thus, the mitochondria play a central role in the pathogenesis pertaining to neuronal disorders. Dysfunction in the mitochondria is an early pathological hallmark of neurological disorders, and its early detection with the help of suitable biomarkers can lead to promising treatment in this area. Thus, the drugs which are targeting mitochondrial dysfunctions are the emerging area of research in connection with neurological disorders. This can be evidenced by the great opportunities for mitigation, diagnosis, and treatment of numerous human disorders that entail mitochondrial dysfunction at the nexus of their pathogenesis. Here, we throw light at the mitochondrial pathologies and indications of dysfunctional mitochondria in PD, AD, and PSP. There is also an insight into the possible therapeutic strategies highlighting the need for mitochondria-based medicine and made an attempt for claiming the prerequisite for the therapy of neurological diseases.
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Affiliation(s)
- Arpita Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, India
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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22
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Talebi M, Kakouri E, Talebi M, Tarantilis PA, Farkhondeh T, İlgün S, Pourbagher-Shahri AM, Samarghandian S. Nutraceuticals-based therapeutic approach: recent advances to combat pathogenesis of Alzheimer's disease. Expert Rev Neurother 2021; 21:625-642. [PMID: 33910446 DOI: 10.1080/14737175.2021.1923479] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanying memory deficits. The available pharmaceutical care has some limitations mostly entailing side effects, shelf-life, and patient's compliance. The momentous implications of nutraceuticals in AD have attracted scientists. Several preclinical studies for the investigation of nutraceuticals have been conducted.Areas covered: This review focuses on the potential use of a nutraceuticals-based therapeutic approach to treat and prevent AD. Increasing knowledge of AD pathogenesis has led to the discovery of new therapeutic targets including pathophysiological mechanisms and various cascades. Hence, the present contribution will attend to the most popular and effective nutraceuticals with proposed brief mechanisms entailing antioxidant, anti-inflammatory, autophagy regulation, mitochondrial homeostasis, and more. Therefore, even though the effectiveness of nutraceuticals cannot be dismissed, it is essential to do further high-quality randomized clinical trials.Expert opinion: According to the potential of nutraceuticals to combat AD as multi-target directed drugs, there is critical importance to assess them as feasible lead compounds for drug discovery and development. To the best of the authors' knowledge, modification of blood-brain barrier permeability, bioavailability, and features of randomized clinical trials should be considered in prospective studies.
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Affiliation(s)
- Marjan Talebi
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Eleni Kakouri
- Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece
| | - Mohsen Talebi
- Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas, United States.,Food Safety Net Services, San Antonio, Texas, United States
| | - Petros A Tarantilis
- Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Selen İlgün
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - Ali Mohammad Pourbagher-Shahri
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Faculty of Pharmacy, Birjand University of Medical Sciences (BUMS), Birjand, Iran
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
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23
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Huang Z, Yan Q, Wang Y, Zou Q, Li J, Liu Z, Cai Z. Role of Mitochondrial Dysfunction in the Pathology of Amyloid-β. J Alzheimers Dis 2021; 78:505-514. [PMID: 33044180 DOI: 10.3233/jad-200519] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Mitochondrial dysfunction has been widely reported in several neurodegenerative disorders, including in the brains of patients with Alzheimer's disease (AD), Parkinson's disease, and Huntington disease. An increasing number of studies have implicated altered glucose and energy metabolism in patients with AD. There is compelling evidence of abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, which play a great significance role in the pathogenesis of AD. Changes in some of the enzyme activities of the mitochondria found in AD have been linked with the pathology of amyloid-β (Aβ). This review highlights the role of mitochondrial function in the production and clearance of Aβ and how the pathology of Aβ leads to a decrease in energy metabolism by affecting mitochondrial function.
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Affiliation(s)
- Zhenting Huang
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China
| | - Qian Yan
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China.,Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
| | - Yangyang Wang
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China
| | - Qian Zou
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China
| | - Jing Li
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China
| | - Zhou Liu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang, Guangdong, China
| | - Zhiyou Cai
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, Chongqing, China
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24
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Kent AC, El Baradie KBY, Hamrick MW. Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6626484. [PMID: 33574977 PMCID: PMC7861926 DOI: 10.1155/2021/6626484] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023]
Abstract
The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.
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Affiliation(s)
- Andrew C. Kent
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- University of Georgia, Athens, GA, USA
| | | | - Mark W. Hamrick
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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25
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Jayatunga DPW, Hone E, Bharadwaj P, Garg M, Verdile G, Guillemin GJ, Martins RN. Targeting Mitophagy in Alzheimer's Disease. J Alzheimers Dis 2020; 78:1273-1297. [PMID: 33285629 DOI: 10.3233/jad-191258] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer's disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.
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Affiliation(s)
- Dona P W Jayatunga
- Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Eugene Hone
- Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Cooperative Research Centre for Mental Health, Carlton, VIC, Australia
| | - Prashant Bharadwaj
- Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Cooperative Research Centre for Mental Health, Carlton, VIC, Australia
| | - Manohar Garg
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.,Riddet Institute, Massey University, Palmerston North, New Zealand
| | - Giuseppe Verdile
- Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Gilles J Guillemin
- Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.,St. Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia
| | - Ralph N Martins
- Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia.,Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia.,School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia.,KaRa Institute of Neurological Diseases, Sydney, NSW, Australia
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26
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Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer's disease. J Neurol Sci 2020; 421:117253. [PMID: 33476985 DOI: 10.1016/j.jns.2020.117253] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 10/21/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid beta (A)] and neurofibrillary tangles (aggregates of tau protein). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than A plaques. Mitochondrial damage plays an important role in AD. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. Elevate reactive oxygen species/reactive nitrogen species production and defective mitochondrial dynamic balance has been suggested to be the reason as well as the consequence of AD related pathology. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagy pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between mitochondrial dysfunctioning, oxidative stress, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on mitochondrial dysfunctioning, oxidative stress, and autophagy. We also discuss the interlink mechanism of these three factors in AD.
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Affiliation(s)
- Vandana Bhatia
- School of Pharmaceutical and Healthcare, CT University, Ludhiana, Punjab, India
| | - Saurabh Sharma
- School of Pharmaceutical Sciences, CT University, Ludhiana, Punjab, India.
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27
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Yang L, Youngblood H, Wu C, Zhang Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 2020; 9:19. [PMID: 32475349 PMCID: PMC7262767 DOI: 10.1186/s40035-020-00197-z] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.
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Affiliation(s)
- Luodan Yang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Hannah Youngblood
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Chongyun Wu
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Quanguang Zhang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
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28
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Vinklarova L, Schmidt M, Benek O, Kuca K, Gunn-Moore F, Musilek K. Friend or enemy? Review of 17β-HSD10 and its role in human health or disease. J Neurochem 2020; 155:231-249. [PMID: 32306391 DOI: 10.1111/jnc.15027] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/26/2020] [Accepted: 04/10/2020] [Indexed: 12/17/2022]
Abstract
17β-hydroxysteroid dehydrogenase (17β-HSD10) is a multifunctional human enzyme with important roles both as a structural component and also as a catalyst of many metabolic pathways. This mitochondrial enzyme has important functions in the metabolism, development and aging of the neural system, where it is involved in the homeostasis of neurosteroids, especially in regard to estradiol, changes in which make it an essential part of neurodegenerative pathology. These roles therefore, indicate that 17β-HSD10 may be a possible druggable target for neurodegenerative diseases including Alzheimer's disease (AD), and in hormone-dependent cancer. The objective of this review was to provide a summary about physiological functions and pathological roles of 17β-HSD10 and the modulators of its activity.
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Affiliation(s)
- Lucie Vinklarova
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Monika Schmidt
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Ondrej Benek
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | | | - Kamil Musilek
- Faculty of Science, Department of Chemistry, University of Hradec Kralove, Hradec Kralove, Czech Republic
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29
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Accorroni A, Rutigliano G, Sabatini M, Frascarelli S, Borsò M, Novelli E, Bandini L, Ghelardoni S, Saba A, Zucchi R, Origlia N. Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from β-Amyloid Toxicity. Thyroid 2020; 30:147-160. [PMID: 31709926 DOI: 10.1089/thy.2019.0255] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background: A novel form of thyroid hormone (TH) signaling is represented by 3-iodothyronamine (T1AM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine-associated receptor 1 (TAAR1), and induces pro-learning and anti-amnestic effects in mice. Dysregulation of TH signaling has long been hypothesized to play a role in Alzheimer's disease (AD). In the present investigation, we explored the neuroprotective role of T1AM in beta amyloid (Aβ)-induced synaptic and behavioral impairment, focusing on the entorhinal cortex (EC), an area that is affected early by AD pathology. Methods: Field potentials were evoked in EC layer II, and long-term potentiation (LTP) was elicited by high frequency stimulation (HFS). T1AM (5 μM) and/or Aβ(1-42) (200 nM), were administered for 10 minutes, starting 5 minutes before HFS. Selective TAAR1 agonist RO5166017 (250 nM) and TAAR1 antagonist EPPTB (5 nM) were also used. The electrophysiological experiments were repeated in EC-slices taken from a mouse model of AD (mutant human amyloid precursor protein [mhAPP], J20 line). We also assessed the in vivo effects of T1AM on EC-dependent associative memory deficits, which were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR1 expression was determined by Western blot, whereas T1AM and its metabolite 3-iodothyroacetic acid (TA1) were assayed by high-performance liquid chromatography coupled to mass spectrometry. Results: We demonstrate the presence of endogenous T1AM and TAAR1 in the EC of wild-type and mhAPP mice. Exposure to Aβ(1-42) inhibited LTP, and T1AM perfusion (at a concentration of 5 μM, leading to an actual concentration in the perfusion buffer ranging from 44 to 298 nM) restored it, whereas equimolar amounts of 3,5,3'-triiodo-L-thyronine (T3) and TA1 were ineffective. The response to T1AM was abolished by the TAAR1 antagonist EPPTB, whereas it was mimicked by the TAAR1 agonist RO5166017. In the EC of APPJ20 mice, LTP could not be elicited, but it was rescued by T1AM. The intra-cerebro-ventricular administration of T1AM (0.89 μg/kg) also restored recognition memory that was impaired in mhAPP mice. Conclusions: Our results suggest that T1AM and TAAR1 are part of an endogenous system that can be modulated to prevent synaptic and behavioral deficits associated with Aβ-related toxicity.
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Affiliation(s)
- Alice Accorroni
- Scuola Superiore di Studi Universitari e di Perfezionamento Sant'Anna, Pisa, Italy
- Institute of Neuroscience of the Italian National Research Council (CNR), Pisa, Italy
| | - Grazia Rutigliano
- Scuola Superiore di Studi Universitari e di Perfezionamento Sant'Anna, Pisa, Italy
| | | | | | - Marco Borsò
- Department of Pathology, University of Pisa, Pisa, Italy
| | - Elena Novelli
- Institute of Neuroscience of the Italian National Research Council (CNR), Pisa, Italy
| | | | | | | | | | - Nicola Origlia
- Institute of Neuroscience of the Italian National Research Council (CNR), Pisa, Italy
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30
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Hassan R, Rabea AA, Ragae A, Sabry D. The prospective role of mesenchymal stem cells exosomes on circumvallate taste buds in induced Alzheimer's disease of ovariectomized albino rats: (Light and transmission electron microscopic study). Arch Oral Biol 2019; 110:104596. [PMID: 31734542 DOI: 10.1016/j.archoralbio.2019.104596] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/17/2019] [Accepted: 10/25/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To elucidate the effect of Alzheimer's disease on the structure of circumvallate papilla taste buds and the possible role of exosomes on the taste buds in Alzheimer's disease. DESIGN Forty two ovariectomized female adult albino rats were utilized and divided into: Group I: received vehicle. Group II: received aluminum chloride to induce Alzheimer's disease. Group III: after the induction of Alzheimer's disease, each rat received single dose of exosomes then left for 4 weeks. The circumvallate papillae were prepared for examination by light and transmission electron microscope. STATISTICAL ANALYSIS histomorphometric data were statistically analyzed. RESULTS Histological examination of circumvallate papilla in Group I showed normal histological features. Group II revealed distorted features. Group III illustrated nearly normal histological features of circumvallate. Silver impregnation results showed apparently great number of heavily impregnated glossopharyngeal nerve fibers in both Groups I & III but markedly decreased in Group II. Synaptophysin-immunoreactivity was strong in Group I, mild in Group II and moderate in Group III. The ultra-structural examination of taste bud cells revealed normal features in Group I, distorted features in Group II and almost normal features in Group III. Statistically highest mean of Synaptophysin-immunoreactivity area% was for Group I, followed by Group III, and the least value was for Group II. CONCLUSIONS Alzheimer's disease has degenerative effects. Bone marrow mesenchymal stem cell (BM-MSC)-derived exosomes have the ability to improve the destructive changes induced by Alzheimer's disease.
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Affiliation(s)
- Rabab Hassan
- Lecturer of Oral Biology, Faculty of Dentistry, Ain Shams University, Cairo, Egypt
| | - Amany A Rabea
- Associate Professor of Oral Biology, Faculty of Oral and Dental Medicine, Future University in Egypt, Cairo, Egypt.
| | - Alyaa Ragae
- Professor of General Histology, Faculty of Oral and Dental Medicine, Future University in Egypt, Cairo, Egypt
| | - Dina Sabry
- Professor of Medical biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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31
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ABAD/17β-HSD10 reduction contributes to the protective mechanism of huperzine a on the cerebral mitochondrial function in APP/PS1 mice. Neurobiol Aging 2019; 81:77-87. [DOI: 10.1016/j.neurobiolaging.2019.05.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 05/18/2019] [Accepted: 05/22/2019] [Indexed: 12/14/2022]
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32
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Hawkins KE, Duchen M. Modelling mitochondrial dysfunction in Alzheimer’s disease using human induced pluripotent stem cells. World J Stem Cells 2019; 11:236-253. [PMID: 31171953 PMCID: PMC6545525 DOI: 10.4252/wjsc.v11.i5.236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/22/2019] [Accepted: 03/26/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells (iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aβ and tau, oxidative stress and mitochondrial dysfunction, sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.
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Affiliation(s)
- Kate Elizabeth Hawkins
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
| | - Michael Duchen
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
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33
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Berberine Alleviates Amyloid β-Induced Mitochondrial Dysfunction and Synaptic Loss. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7593608. [PMID: 31191803 PMCID: PMC6525905 DOI: 10.1155/2019/7593608] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 03/12/2019] [Indexed: 11/18/2022]
Abstract
Synaptic structural and functional damage is a typical pathological feature of Alzheimer's disease (AD). Normal axonal mitochondrial function and transportation are vital to synaptic function and plasticity because they are necessary for maintaining cellular energy supply and regulating calcium and redox signalling as well as synaptic transmission and vesicle release. Amyloid-β (Aβ) accumulation is another pathological hallmark of AD that mediates synaptic loss and dysfunction by targeting mitochondria. Therefore, it is important to develop strategies to protect against synaptic mitochondrial damage induced by Aβ. The present study examined the beneficial effects of berberine, a natural isoquinoline alkaloid extracted from the traditional medicinal plant Coptis chinensis, on Aβ-induced mitochondrial and synaptic damage in primary cultured hippocampal neurons. We demonstrate that berberine alleviates axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in cultured hippocampal neurons. Although the underlying protective mechanism remains to be elucidated, the data suggest that the effects of berberine were in part related to its potent antioxidant activity. These findings highlight the neuroprotective and specifically mitoprotective effects of berberine treatment under conditions of Aβ enrichment.
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Islam BU, Jabir NR, Tabrez S. The role of mitochondrial defects and oxidative stress in Alzheimer's disease. J Drug Target 2019; 27:932-942. [PMID: 30775938 DOI: 10.1080/1061186x.2019.1584808] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Alzheimer's disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder. Recent reports suggest that it affects more than 36 million people worldwide and accounts 60-80% of all cases of dementia. It is characterised by aberrations of multiple interactive systems and pathways, which ultimately lead to memory loss and cognitive dysfunction. The exact mechanisms and initial triggering factors that underpin the known pathological defects in AD remain to be fully elucidated. In addition, an effective treatment strategy to reduce the progression of AD is yet to be achieved. In the light of above-mentioned facts, our article deals with the exploration of the mitochondrial defect and oxidative stress leading to this devastating disease. In this communication, we have highlighted specific mitochondrial and antioxidant-directed approach to ameliorate and manage AD. Nonetheless, new approaches should also be investigated that could tackle various molecular events involved in AD pathogenicity.
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Affiliation(s)
- Badar Ul Islam
- a Department of Biochemistry, J N Medical College, Faculty of Medicine, Aligarh Muslim University , Aligarh , India
| | - Nasimudeen R Jabir
- b King Fahd Medical Research Center, King Abdulaziz University , Jeddah , Saudi Arabia.,c Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University , Jeddah , Saudi Arabia
| | - Shams Tabrez
- b King Fahd Medical Research Center, King Abdulaziz University , Jeddah , Saudi Arabia.,c Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University , Jeddah , Saudi Arabia
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Morsy A, Trippier PC. Current and Emerging Pharmacological Targets for the Treatment of Alzheimer's Disease. J Alzheimers Dis 2019; 72:S145-S176. [PMID: 31594236 DOI: 10.3233/jad-190744] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
No cure or disease-modifying therapy for Alzheimer's disease (AD) has yet been realized. However, a multitude of pharmacological targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathological hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N-methyl-D-aspartate receptor blockade treatments that are clinically approved for the symptomatic treatment of AD. Additional targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of 'sensitive targets' that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target's function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our analysis to targets that have emerged in the last decade and targets that have been validated using small molecules in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and critical targets suitable for small molecule drug intervention.
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Affiliation(s)
- Ahmed Morsy
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Paul C Trippier
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
- UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, NE, USA
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Morsy A, Trippier PC. Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer’s Disease. J Med Chem 2018; 62:4252-4264. [DOI: 10.1021/acs.jmedchem.8b01530] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ahmed Morsy
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, United States
| | - Paul C. Trippier
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, United States
- Center for Chemical Biology, Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States
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Kalani K, Yan SF, Yan SS. Mitochondrial permeability transition pore: a potential drug target for neurodegeneration. Drug Discov Today 2018; 23:1983-1989. [PMID: 30081095 PMCID: PMC6449145 DOI: 10.1016/j.drudis.2018.08.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 07/17/2018] [Accepted: 08/01/2018] [Indexed: 12/21/2022]
Abstract
The mitochondrial permeability transition pore (mPTP) has been considered a key contributor to cell death, inducing the process in several major neurodegenerative diseases. To date, the molecular nature of the mPTP remains confounding but its significance is universally acknowledged. Several targets have been screened and inhibition of mPTP has emerged as an attractive field for researchers. Nowadays, in silico-directed studies help to explore new small molecules targeting the mPTP to improve their drug-like properties and bioactivity. Here, we briefly summarize the role of mPTP in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson disease (PD), and Huntington's disease (HD), and discusses current and future potential therapeutic targets.
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Affiliation(s)
- Komal Kalani
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shi Fang Yan
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shirley ShiDu Yan
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
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Tucker D, Lu Y, Zhang Q. From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Mol Neurobiol 2018; 55:5137-5153. [PMID: 28840449 PMCID: PMC5826781 DOI: 10.1007/s12035-017-0712-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 08/07/2017] [Indexed: 12/23/2022]
Abstract
Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used classically for the treatment of malaria, methemoglobinemia, and carbon monoxide poisoning, as well as a histological dye. Its role in the mitochondria, however, has elicited much of its renewed interest in recent years. MB can reroute electrons in the mitochondrial electron transfer chain directly from NADH to cytochrome c, increasing the activity of complex IV and effectively promoting mitochondrial activity while mitigating oxidative stress. In addition to its beneficial effect on mitochondrial protection, MB is also known to have robust effects in mitigating neuroinflammation. Mitochondrial dysfunction has been identified as a seemingly unifying pathological phenomenon across a wide range of neurodegenerative disorders, which thus positions methylene blue as a promising therapeutic. In both in vitro and in vivo studies, MB has shown impressive efficacy in mitigating neurodegeneration and the accompanying behavioral phenotypes in animal models for such conditions as stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review summarizes recent work establishing MB as a promising candidate for neuroprotection, with particular emphasis on the contribution of mitochondrial function to neural health. Furthermore, this review will briefly examine the link between MB, neurogenesis, and improved cognition in respect to age-related cognitive decline.
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Affiliation(s)
- Donovan Tucker
- Department of Neuroscience and Regenerative Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Yujiao Lu
- Department of Neuroscience and Regenerative Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA
| | - Quanguang Zhang
- Department of Neuroscience and Regenerative Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
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Beckert B, Acker-Palmer A, Volknandt W. Aβ42 oligomers impair the bioenergetic activity in hippocampal synaptosomes derived from APP-KO mice. Biol Chem 2018; 399:453-465. [PMID: 29337689 DOI: 10.1515/hsz-2017-0238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 12/20/2017] [Indexed: 11/15/2022]
Abstract
Employing hippocampal synaptosomes from amyloid precursor protein (APP)-deleted mice we analyzed the immediate effects of amyloid beta peptide 42 (Aβ42) peptide in its oligomeric or fibrillar assembly or of soluble amyloid precursor protein alpha (sAPPα) protein on their bioenergetic activity. Upon administration of oligomeric Aβ42 peptide for 30 min we observed a robust decrease both in mitochondrial activity and in mitochondrial membrane potential (MMP). In contrast the respective fibrillary or scrambled peptides showed no effect, indicating that inhibition strictly depends on the oligomerization status of the peptide. Hippocampal synaptosomes from old APP-KO mice revealed a further reduction of their already impaired bioenergetic activity upon incubation with 10 μm Aβ42 peptide. In addition we evaluated the influence of the sAPPα protein on mitochondrial activity of hippocampal synaptosomes derived from young or old APP-KO animals. In neither case 20 nm nor 200 nm sAPPα protein had an effect on mitochondrial metabolic activity. Our findings demonstrate that hippocampal synaptosomes derived from APP-KO mice are a most suitable model system to evaluate the impact of Aβ42 peptide on its bioenergetic activity and to further elucidate the molecular mechanisms underlying the impairments by oligomeric Aβ42 on mitochondrial function. Our data demonstrate that extracellular Aβ42 peptide is taken up into synaptosomes where it immediately attenuates mitochondrial activity.
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Affiliation(s)
- Benedikt Beckert
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt/Main, Germany
| | - Amparo Acker-Palmer
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt/Main, Germany
- Max Planck Institute for Brain Research, Max-von-Laue-Str. 4, D-60438 Frankfurt/Main, Germany
| | - Walter Volknandt
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt/Main, Germany
- Department for Molecular and Cellular Neurobiology, Goethe University Frankfurt, Max-von-Laue-Str. 13, D-60438 Frankfurt, Germany
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Yan SF, Akhter F, Sosunov AA, Yan SS. Identification and Characterization of Amyloid-β Accumulation in Synaptic Mitochondria. Methods Mol Biol 2018; 1779:415-433. [PMID: 29886547 DOI: 10.1007/978-1-4939-7816-8_25] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
Abstract
Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Accumulation of amyloid beta-peptide (Aβ) in mitochondria, particularly in synaptic mitochondria, potentiates and amplifies synaptic injury and disruption of synaptic transmission, leading to synaptic dysfunction and ultimately to synaptic failure. Thus, determination of the presence and levels of Aβ in synaptic mitochondria associated with amyloid pathology is important for studying mitochondrial amyloid pathology. Here, we present a detailed methodology for the isolation of synaptic mitochondria from brain tissues and the determination of Aβ levels in the isolated mitochondria as well as ultrastructural localization of synaptic mitochondrial Aβ. These methods have been used successfully for the identification and characterization of Aβ accumulation in synaptic mitochondria from mouse brains derived from transgenic AD mouse model. Additionally, we comprehensively discuss the sample preparation, experimental details, our unique procedures, optimization of parameters, and troubleshooting.
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Affiliation(s)
- Shi Fang Yan
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
| | - Firoz Akhter
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA
| | | | - Shirley ShiDu Yan
- Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
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42
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Kawamata H, Manfredi G. Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. J Cell Biol 2017; 216:3917-3929. [PMID: 29167179 PMCID: PMC5716291 DOI: 10.1083/jcb.201709172] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/08/2017] [Accepted: 11/10/2017] [Indexed: 12/12/2022] Open
Abstract
Mitochondria participate in essential processes in the nervous system such as energy and intermediate metabolism, calcium homeostasis, and apoptosis. Major neurodegenerative diseases are characterized pathologically by accumulation of misfolded proteins as a result of gene mutations or abnormal protein homeostasis. Misfolded proteins associate with mitochondria, forming oligomeric and fibrillary aggregates. As mitochondrial dysfunction, particularly of the oxidative phosphorylation system (OXPHOS), occurs in neurodegeneration, it is postulated that such defects are caused by the accumulation of misfolded proteins. However, this hypothesis and the pathological role of proteinopathies in mitochondria remain elusive. In this study, we critically review the proposed mechanisms whereby exemplary misfolded proteins associate with mitochondria and their consequences on OXPHOS.
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Affiliation(s)
- Hibiki Kawamata
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
| | - Giovanni Manfredi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
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The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2973-2986. [PMID: 28768149 DOI: 10.1016/j.bbadis.2017.07.031] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 07/13/2017] [Accepted: 07/28/2017] [Indexed: 02/06/2023]
Abstract
A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE ε3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member α-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.
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Viswanath ANI, Kim T, Jung SY, Lim SM, Pae AN. In silico-designed novel non-peptidic ABAD L D hot spot mimetics reverse Aβ-induced mitochondrial impairments in vitro. Chem Biol Drug Des 2017; 90:1041-1055. [PMID: 28660722 DOI: 10.1111/cbdd.13065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/25/2017] [Accepted: 06/04/2017] [Indexed: 02/05/2023]
Abstract
Present work aimed to introduce non-peptidic ABAD loop D (LD ) hot spot mimetics as ABAD-Aβ inhibitors. A full-length atomistic model of ABAD-Aβ complex was built as a scaffold to launch the lead design and its topology later verified by cross-checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Aβ-binding LD residues-Tyr101, Thr108, and Thr110-were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA-based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC50 of 4.4 ± 0.3 and 9.6 ± 0.1 μm, respectively. They productively reversed Aβ-induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC-1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of LD hot spot-centric in silico scheme to discover novel compounds with promising ABAD-Aβ inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics.
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Affiliation(s)
- Ambily Nath Indu Viswanath
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.,Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea
| | - TaeHun Kim
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.,Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea
| | - Seo Yun Jung
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea
| | - Sang Min Lim
- Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea.,Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, Korea
| | - Ae Nim Pae
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.,Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea
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Korábečný J, Nepovimová E, Cikánková T, Špilovská K, Vašková L, Mezeiová E, Kuča K, Hroudová J. Newly Developed Drugs for Alzheimer's Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission. Neuroscience 2017; 370:191-206. [PMID: 28673719 DOI: 10.1016/j.neuroscience.2017.06.034] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 11/18/2022]
Abstract
Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.
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Affiliation(s)
- Jan Korábečný
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic
| | - Eugenie Nepovimová
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Tereza Cikánková
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
| | - Katarína Špilovská
- National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Třebešská 1575, 500 01 Hradec Králové, Czech Republic
| | - Lucie Vašková
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Eva Mezeiová
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic; Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
| | - Kamil Kuča
- Biomedical Research Centre, University Hospital Hradec Kralové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanského 62, 500 03 Hradec Králové, Czech Republic
| | - Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00 Prague 2, Czech Republic.
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Akhter F, Chen D, Yan SF, Yan SS. Mitochondrial Perturbation in Alzheimer's Disease and Diabetes. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 146:341-361. [PMID: 28253990 DOI: 10.1016/bs.pmbts.2016.12.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mitochondria are well-known cellular organelles that play a vital role in cellular bioenergetics, heme biosynthesis, thermogenesis, calcium homeostasis, lipid catabolism, and other metabolic activities. Given the extensive role of mitochondria in cell function, mitochondrial dysfunction plays a part in many diseases, including diabetes and Alzheimer's disease (AD). In most cases, there is overwhelming evidence that impaired mitochondrial function is a causative factor in these diseases. Studying mitochondrial function in diseased cells vs healthy cells may reveal the modified mechanisms and molecular components involved in specific disease states. In this chapter, we provide a concise overview of the major recent findings on mitochondrial abnormalities and their link to synaptic dysfunction relevant to neurodegeneration and cognitive decline in AD and diabetes. Our increased understanding of the role of mitochondrial perturbation indicates that the development of specific small molecules targeting aberrant mitochondrial function could provide therapeutic benefits for the brain in combating aging-related dementia and neurodegenerative diseases by powering up brain energy and improving synaptic function and transmission.
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Affiliation(s)
- F Akhter
- School of Pharmacy, Higuchi Bioscience Center, University of Kansas, Lawrence, KS, United States
| | - D Chen
- School of Pharmacy, Higuchi Bioscience Center, University of Kansas, Lawrence, KS, United States
| | - S F Yan
- School of Pharmacy, Higuchi Bioscience Center, University of Kansas, Lawrence, KS, United States
| | - S S Yan
- School of Pharmacy, Higuchi Bioscience Center, University of Kansas, Lawrence, KS, United States.
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Hroch L, Guest P, Benek O, Soukup O, Janockova J, Dolezal R, Kuca K, Aitken L, Smith TK, Gunn-Moore F, Zala D, Ramsay RR, Musilek K. Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment. Bioorg Med Chem 2017; 25:1143-1152. [DOI: 10.1016/j.bmc.2016.12.029] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/18/2016] [Indexed: 01/03/2023]
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48
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Han J, Qu Q, Qiao J, Zhang J. Vincamine Alleviates Amyloid-β 25-35 Peptides-induced Cytotoxicity in PC12 Cells. Pharmacogn Mag 2017; 13:123-128. [PMID: 28216895 PMCID: PMC5307895 DOI: 10.4103/0973-1296.196309] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective: Vincamine is a plant alkaloid used clinically as a peripheral vasodilator that increases cerebral blood flow and oxygen and glucose utilization by neural tissue to combat the effect of aging. The main purpose of the present study is to investigate the influence of vincamine on amyloid-β 25–35 (Aβ25–35) induced cytotoxicity, to gain a better understanding of the neuroprotective effects of this clinically used anti-Alzheimer's disease drug. Materials and Methods: Oxidative stress was assessed by measuring malondialdehyde, glutathione, and superoxide dismutase (SOD) levels. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis detection was performed using an Annexin-V-FITC Apoptosis Detection Kit. The production of reactive oxygen species (ROS) was determined using an ROS Assay Kit. Western blot detection was carried out to detect the protein expression. Results: Our studies showed that pretreatment with vincamine could reduce Aβ25–35 induced oxidative stress. Vincamine markedly inhibited cell apoptosis dose-dependently. More importantly, vincamine increased the phosphatidylinositol-3 kinase (PI3K)/Akt and Bcl-2 family protein ratios on preincubation with cells for 2 h. Conclusion: Above observation led us to assume that one possible mechanism of vincamine protects Aβ25-35-induced cell death could be through upregulation of SOD and activation of the PI3K/Akt pathway. SUMMARY
Vincamine ameliorates amyloid-β 25–35 (Aβ25–35) peptides induced cytotoxicity in PC12 cells Vincamine reduces Aβ 25–35 peptides induced apoptosis of PC12 cells Vincamine activates the phosphatidylinositol-3 kinase/Akt pathway Vincamine up-regulates the superoxide dismutase. Abbreviation used: Aβ25-35: Amyloid-β 25-35; AD: Alzheimer's disease; BCA: Bicinchoninic acid; GSH: glutathione; PBS: Phosphate buffered solution; SDS: Sodium dodecylsulphate; SOD: Superoxide dismutase
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Affiliation(s)
- Jianfeng Han
- Department of Neurology, The First Clinical Hospital of Xian Jiaotong University, Xian 710061, P.R. China
| | - Qiumin Qu
- Department of Neurology, The First Clinical Hospital of Xian Jiaotong University, Xian 710061, P.R. China
| | - Jin Qiao
- Department of Neurology, The First Clinical Hospital of Xian Jiaotong University, Xian 710061, P.R. China
| | - Jie Zhang
- Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Fang D, Zhang Z, Li H, Yu Q, Douglas JT, Bratasz A, Kuppusamy P, Yan SS. Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer's disease Mouse Brain. J Alzheimers Dis 2016; 51:571-80. [PMID: 26890765 DOI: 10.3233/jad-150917] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.
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Affiliation(s)
- Du Fang
- Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA
| | - Zhihua Zhang
- School of Life Sciences, Beijing Normal University, Beijing, China.,Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA
| | - Hang Li
- School of Life Sciences, Beijing Normal University, Beijing, China
| | - Qing Yu
- Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du, China
| | - Justin T Douglas
- Nuclear Magnetic Resonance Laboratory, Molecular Structures Group, School of Pharmacy, University of Kansas, Lawrence, KS, USA
| | - Anna Bratasz
- Small Animal Imaging Core, Ohio State University, Columbus, OH, USA
| | - Periannan Kuppusamy
- Department of Radiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA
| | - Shirley ShiDu Yan
- Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA
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50
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Wilkins HM, Swerdlow RH. Amyloid precursor protein processing and bioenergetics. Brain Res Bull 2016; 133:71-79. [PMID: 27545490 DOI: 10.1016/j.brainresbull.2016.08.009] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 08/15/2016] [Accepted: 08/17/2016] [Indexed: 02/08/2023]
Abstract
The processing of amyloid precursor protein (APP) to amyloid beta (Aβ) is of great interest to the Alzheimer's disease (AD) field. Decades of research define how APP is altered to form Aβ, and how Aβ generates oligomers, protofibrils, and fibrils. Numerous signaling pathways and changes in cell physiology are known to influence APP processing. Existing data additionally indicate a relationship exists between mitochondria, bioenergetics, and APP processing. Here, we review data that address whether mitochondrial function and bioenergetics modify APP processing and Aβ production.
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Affiliation(s)
- Heather M Wilkins
- Department of Neurology University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA
| | - Russell H Swerdlow
- Department of Neurology University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS USA.
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