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Neto DCF, Diz JSF, Guimarães SJA, Dos Santos EM, Nascimento MDDSB, de Azevedo-Santos APS, França TCC, LaPlante SR, do Nascimento CJ, Lima JA. Guanylhydrazone and semicarbazone derivatives as potential prototypes for the design of cholinesterase inhibitors against Alzheimer's disease: biological evaluation and molecular modeling studies. Chem Biol Interact 2025; 415:111515. [PMID: 40246050 DOI: 10.1016/j.cbi.2025.111515] [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: 09/26/2024] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (1, 2, and 3) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound 2 (phenanthrenequinone) demonstrated superior inhibitory potency with an IC50 of 0.68 μM, compared to compound 1 (acridinone) with an IC50 of 3.87 μM, and compound 3 (benzodioxole) with an IC50 of 101.7 μM. In contrast, semicarbazones (4 and 5) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds 3, 4, and 5 may be more effective in the early phase, when AChE activity remains high; compound 1 could be useful in the intermediate phase; and compound 2 appears particularly promising for the severe phase, when BChE plays a more dominant role.
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Affiliation(s)
- Denise Cristian Ferreira Neto
- Medicinal Chemistry Group, Department of Chemistry, Military Institute of Engineering, Praça General Tibúrcio 80, 22290-270, Rio de Janeiro, RJ, Brazil; Department of Chemistry, Federal University of Roraima, Av. Cap. Ene Garcês, 2413, 69310-000, Boa Vista, Roraima, Brazil.
| | - Joyce Sobreiro Francisco Diz
- Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering (IME), Praça General Tibúrcio 80, 22290-270, Rio de Janeiro, Brazil; Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Av. das Américas 28705, Área 4, 23020-470, Rio de Janeiro, RJ, Brazil
| | - Sulayne Janayna Araújo Guimarães
- Laboratory for Applied Cancer Immunology, Biological and Health Sciences Center, Federal University of Maranhão, Avenida dos Portugueses, 1966, Bacanga, 65080-805, São Luís, Maranhão, Brazil
| | - Eduardo Mendes Dos Santos
- Federal University of Maranhão, Postgraduate Program in Adult Health (PPGSAD), Avenida dos Portugueses, 1966, Bacanga, 65080-805, São Luís, Maranhão, Brazil
| | | | - Ana Paula Silva de Azevedo-Santos
- Laboratory for Applied Cancer Immunology, Biological and Health Sciences Center, Federal University of Maranhão, Avenida dos Portugueses, 1966, Bacanga, 65080-805, São Luís, Maranhão, Brazil
| | - Tanos Celmar Costa França
- Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering (IME), Praça General Tibúrcio 80, 22290-270, Rio de Janeiro, Brazil; Université de Québec, INRS - Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec, H7V 1B7, Canada; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic
| | - Steven R LaPlante
- Université de Québec, INRS - Centre Armand-Frappier Santé Biotechnologie, 531 boulevard des Prairies, Laval, Québec, H7V 1B7, Canada
| | - Claudia Jorge do Nascimento
- Institute of Biosciences, Federal University of the State of Rio de Janeiro, Av. Pasteur, 296, Urca, 22290-250, Rio de Janeiro, Brazil
| | - Josélia Alencar Lima
- Federal University of Maranhão, Postgraduate Program in Adult Health (PPGSAD), Avenida dos Portugueses, 1966, Bacanga, 65080-805, São Luís, Maranhão, Brazil.
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Sidoryk-Węgrzynowicz M, Adamiak K, Strużyńska L. Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders. Int J Mol Sci 2024; 25:12448. [PMID: 39596513 PMCID: PMC11595158 DOI: 10.3390/ijms252212448] [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: 10/29/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
The abnormal deposition and intercellular propagation of disease-specific protein play a central role in the pathogenesis of many neurodegenerative disorders. Recent studies share the common observation that the formation of protein oligomers and subsequent pathological filaments is an essential step for the disease. Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) are neurodegenerative diseases characterized by the aggregation of the α-synucleinprotein in neurons and/or in oligodendrocytes (glial cytoplasmic inclusions), neuronal loss, and astrogliosis. A similar mechanism of protein Tau-dependent neurodegeneration is a major feature of tauopathies, represented by Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PD). The specific inhibition of the protein misfolding and their interneuronal spreading represents a promising therapeutic strategy against both disease pathology and progression. The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation.
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Affiliation(s)
- Marta Sidoryk-Węgrzynowicz
- Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, 02-106 Warsaw, Poland; (K.A.); (L.S.)
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Rezaul Islam M, Akash S, Murshedul Islam M, Sarkar N, Kumer A, Chakraborty S, Dhama K, Ahmed Al-Shaeri M, Anwar Y, Wilairatana P, Rauf A, Halawani IF, Alzahrani FM, Khan H. Alkaloids as drug leads in Alzheimer's treatment: Mechanistic and therapeutic insights. Brain Res 2024; 1834:148886. [PMID: 38582413 DOI: 10.1016/j.brainres.2024.148886] [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: 02/10/2024] [Revised: 03/22/2024] [Accepted: 03/23/2024] [Indexed: 04/08/2024]
Abstract
Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Shopnil Akash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Mohammed Murshedul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Nadia Sarkar
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka 1216, Bangladesh
| | - Ajoy Kumer
- Laboratory of Computational Research for Drug Design and Material Science, Department of Chemistry, College of Arts and Sciences IUBAT-International University of Business Agriculture and Technology, 4 Embankment Drive Road, Sector 10, Uttara Model Town, Dhaka 1230, Bangladesh; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Sandip Chakraborty
- State Disease Investigation Laboratory, ARDD, Abhoynagar, Agartala, West Tripura, Pin-799005, India
| | - Kuldeep Dhama
- Division of Pathology, Indian Veterinary Research Institute (IVRI) Izatnagar-243 122, Bareilly, Uttar Pradesh, India
| | - Majed Ahmed Al-Shaeri
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21441, Kingdom of Saudi Arabia
| | - Yasir Anwar
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21441, Kingdom of Saudi Arabia
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan
| | - Ibrahim F Halawani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Fuad M Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200 Mardan, Pakistan.
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Samiee-Rad F, Ghasemi F, Bahadoran E, Sofiabadi M, Shalbaf Z, Taherkhani A, Gheibi N. The effect of topical 0.5% humic acid gel on male rats with skin ulcer. J Cutan Aesthet Surg 2024; 17:131-136. [PMID: 38800807 PMCID: PMC11126225 DOI: 10.4103/jcas.jcas_104_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024] Open
Abstract
Background Humic derivatives have antibacterial and anti-inflammatory properties. Aim This study aimed to assess the experimental wound-healing effect of 0.5% humic acid gel. Materials and Methods A full-thickness skin wound was created on the dorsal side of 24 Sprague Dawley male rats (220-250 g). The animals were then randomly divided into the control, sham, and experimental groups. Skin wounds were bandaged daily using sterile gauze dipped in normal saline, carboxymethylcellulose, and 0.5% humic acid for 21 days. The wound-healing rate was evaluated grossly and histologically at various time intervals post-injury. Results Wound-healing percentage was significantly higher in the gel treatment group at all time points (P < 0.05). The mean number of inflammatory cells was significantly lower in the humic acid gel group than in the other groups (P < 0.001). Moreover, the number of new vascular cells and fibroblasts were significantly increased in the humic acid gel compared to the control (P < 0.001). Conclusion These data confirmed that 0.5% humic acid gel accelerates wound healing, probably by anti-inflammatory effects, as well as by promoting vascular and fibroblast proliferation. Therefore, the humic acid gel may be used to improve wound care.
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Affiliation(s)
- Fatemeh Samiee-Rad
- Pathobiology Department, Metabolic Disease Research Center, Research Institute for Non-communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Fatemeh Ghasemi
- Department of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Ensiyeh Bahadoran
- Department of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohammad Sofiabadi
- Physiology Department, Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Shalbaf
- Department of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Arman Taherkhani
- Department of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Nematollah Gheibi
- Biophysics, Biochemistry & Genetics Department, Cellular and Molecular Research Center, Research Institute for Non-communicable Diseases, Qazvin, Iran
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Babashpour-Asl M, kaboudi PS, Barez SR. Therapeutic and medicinal effects of snowdrop ( Galanthus spp.) in Alzheimer's disease: A review. JOURNAL OF EDUCATION AND HEALTH PROMOTION 2023; 12:128. [PMID: 37397105 PMCID: PMC10312406 DOI: 10.4103/jehp.jehp_451_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/13/2022] [Indexed: 07/04/2023]
Abstract
Genus Galanthus (Amaryllidaceae) is an early spring flowering bulbous plant. Galanthus species contain alkaloids that have shown pharmacological activity. Galanthamine is an alkaloid that was extracted from Galanthus and other Amaryllidaceae. Owing to its acetylcholinesterase (AChE) inhibitory activity, galanthamine is used and marketed to treat Alzheimer's disease (AD). The aim of the present study, while introducing the botanical and pharmacological characteristics and various aspects of the medicinal plant Galanthus, is to emphasize the effect of this plant in the treatment of AD. In this web-based study in 2021, articles indexed in scientific databases in English language, including ISI Web of Knowledge, PubMed, Scopus, MedLib, Medknow, SID, ISC, and also articles and e-books published in Springer, Elsevier, John Wiley and Sons, and Taylor and Francis were evaluated from 1990 to 2021, using the following keywords: "Galanthus" "galanthamine," "Alzheimer's disease." Amaryllidaceae-type alkaloids possess an anticholinesterase activity. The most studied Galanthus alkaloid, galanthamine, is a long-acting, selective, reversible, competitive inhibitor of AChE and an allosteric modulator of the neuronal nicotinic receptor for acetylcholine (ACh). Owing to its AChE inhibitory activity, galanthamine is used to treat certain stages of AD. Galantamine can act as a parasympathomimetic agent, especially as a reversible cholinesterase inhibitor. Galantamine is not structurally associated with other AChE inhibitors. Hence, its proposed mechanism of action involves the reversible inhibition of AChE, preventing hydrolysis of ACh that results in an increased concentration of ACh at cholinergic synapses.
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Affiliation(s)
- Marzieh Babashpour-Asl
- Department of Horticultural Science, Maragheh Branch, Islamic Azad University, Maragheh, Iran
| | | | - Shekufe Rezghi Barez
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Bittar A, Al-Lahham R, Bhatt N, Moore K, Montalbano M, Jerez C, Fung L, McAllen S, Ellsworth A, Kayed R. Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner. J Alzheimers Dis 2022; 90:1103-1122. [DOI: 10.3233/jad-220518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. Objective: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. Methods: Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. Results: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo. Conclusion: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.
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Affiliation(s)
- Alice Bittar
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Rabab Al-Lahham
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Nemil Bhatt
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kenya Moore
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Mauro Montalbano
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Cynthia Jerez
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Leiana Fung
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | | | - Anna Ellsworth
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Rakez Kayed
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
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Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice: An In Vitro, In Vivo and Integrated Computational Approach. Brain Sci 2022; 12:brainsci12060731. [PMID: 35741617 PMCID: PMC9221371 DOI: 10.3390/brainsci12060731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/28/2022] [Accepted: 05/31/2022] [Indexed: 02/05/2023] Open
Abstract
Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (F1–F5) were previously synthesized from substituted O-hydroxy acetophenone and substituted chloro-benzaldehydes. The titled compounds F1–F5 in the present study were evaluated for their anticholinesterase potential (against AChE and BuChE). The obtained results were then validated through a molecular docking approach. Compound F5 was found to be the most potent inhibitor of AChE (IC50 = 98.42 ± 0.97 µg/mL) followed by compound F4, whereas compound F2 was found to be the most promising inhibitor of BuChE (IC50 = 105.20 ± 1.43 µg/mL) among the tested compounds. The molecular docking analysis revealed a similar trend in the binding affinity of compounds with the targeted enzymes and found them to be capable of forming highly stable complexes with both receptors. The selected compounds were further subjected to in vivo assessment of cognitive function in a scopolamine-induced amnesic animal model, in which almost all compounds F1–F5 significantly attenuated the amnesic effects as evaluated through Y-Maze Paradigm and novel object discrimination (NOD) tasks, findings that were further supported by ex vivo experimental results. Among (F1–F5), F5 showed significant anti-amnesic effects in scopolamine-induced amnesic models and ameliorated the memory loss in behavioral model studies as compared to counterparts. In ex vivo study, noteworthy protection from oxidative stress in the brains of scopolamine-induced amnesic mice was also recorded for F5. These findings also confirmed that there were no significant differences among the in vivo and ex vivo results after administration of F1–F5 (7.5 or 15 mg/kg) or donepezil (2 mg/kg). These synthesized flavonoids could serve as potential candidates for new neuroprotective and nootropic drugs. However, further studies are needed to validate their observed potential in other animal models as well.
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Jiang L, Lin W, Zhang C, Ash PEA, Verma M, Kwan J, van Vliet E, Yang Z, Cruz AL, Boudeau S, Maziuk BF, Lei S, Song J, Alvarez VE, Hovde S, Abisambra JF, Kuo MH, Kanaan N, Murray ME, Crary JF, Zhao J, Cheng JX, Petrucelli L, Li H, Emili A, Wolozin B. Interaction of tau with HNRNPA2B1 and N 6-methyladenosine RNA mediates the progression of tauopathy. Mol Cell 2021; 81:4209-4227.e12. [PMID: 34453888 PMCID: PMC8541906 DOI: 10.1016/j.molcel.2021.07.038] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/14/2021] [Accepted: 07/28/2021] [Indexed: 12/12/2022]
Abstract
The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.
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Affiliation(s)
- Lulu Jiang
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Weiwei Lin
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Peter E A Ash
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Mamta Verma
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Julian Kwan
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Emily van Vliet
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Zhuo Yang
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Anna Lourdes Cruz
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Samantha Boudeau
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Brandon F Maziuk
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Shuwen Lei
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Jaehyup Song
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Victor E Alvarez
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Stacy Hovde
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Jose F Abisambra
- Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA
| | - Min-Hao Kuo
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
| | - Nicholas Kanaan
- Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Melissa E Murray
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - John F Crary
- Department of Pathology, Mount Sinai Medical Center, New York, NY 10029, USA
| | - Jian Zhao
- Department of Electrical and Computer Engineering, Boston University, Boston, MA 02459, USA
| | - Ji-Xin Cheng
- Department of Electrical and Computer Engineering, Boston University, Boston, MA 02459, USA
| | | | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Andrew Emili
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Benjamin Wolozin
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Center for Neurophotonics, Boston University, Boston, MA 02215, USA; Center for Systems Neuroscience, Boston University, Boston, MA 02215, USA.
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Calfio C, Gonzalez A, Singh SK, Rojo LE, Maccioni RB. The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer's Disease. J Alzheimers Dis 2021; 77:33-51. [PMID: 32651325 DOI: 10.3233/jad-200443] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer's disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics' pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence.
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Affiliation(s)
- Camila Calfio
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Andrea Gonzalez
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Sandeep Kumar Singh
- Indian Scientific Education and Technology Foundation, Lucknow, India.,Centre of Biomedical Research (CBMR), Lucknow, India
| | - Leonel E Rojo
- Department of Biology, University of Santiago, Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile.,Department of Neurology, Faculty of Medicine, University of Chile, Santiago, Chile
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10
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Living with the enemy: from protein-misfolding pathologies we know, to those we want to know. Ageing Res Rev 2021; 70:101391. [PMID: 34119687 DOI: 10.1016/j.arr.2021.101391] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/19/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.
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11
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Lo CH. Recent advances in cellular biosensor technology to investigate tau oligomerization. Bioeng Transl Med 2021; 6:e10231. [PMID: 34589603 PMCID: PMC8459642 DOI: 10.1002/btm2.10231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Tau is a microtubule binding protein which plays an important role in physiological functions but it is also involved in the pathogenesis of Alzheimer's disease and related tauopathies. While insoluble and β-sheet containing tau neurofibrillary tangles have been the histopathological hallmark of these diseases, recent studies suggest that soluble tau oligomers, which are formed prior to fibrils, are the primary toxic species. Substantial efforts have been made to generate tau oligomers using purified recombinant protein strategies to study oligomer conformations as well as their toxicity. However, no specific toxic tau species has been identified to date, potentially due to the lack of cellular environment. Hence, there is a need for cell-based models for direct monitoring of tau oligomerization and aggregation. This review will summarize the recent advances in the cellular biosensor technology, with a focus on fluorescence resonance energy transfer, bimolecular fluorescence complementation, and split luciferase complementation approaches, to monitor formation of tau oligomers and aggregates in living cells. We will discuss the applications of the cellular biosensors in examining the heterogeneous tau conformational ensembles and factors affecting tau self-assembly, as well as detecting cell-to-cell propagation of tau pathology. We will also compare the advantages and limitations of each type of tau biosensors, and highlight their translational applications in biomarker development and therapeutic discovery.
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Affiliation(s)
- Chih Hung Lo
- Department of Neurology, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
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12
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Andrade V, Cortés N, Pastor G, Gonzalez A, Ramos-Escobar N, Pastene E, Rojo LE, Maccioni RB. N-Acetyl Cysteine and Catechin-Derived Polyphenols: A Path Toward Multi-Target Compounds Against Alzheimer's Disease. J Alzheimers Dis 2021; 75:1219-1227. [PMID: 32390631 DOI: 10.3233/jad-200067] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to "damage signals". The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection. OBJECTIVE To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives. METHODS We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC. RESULTS We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway. CONCLUSION EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.
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Affiliation(s)
- Víctor Andrade
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile
| | - Nicole Cortés
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile
| | - Gabriela Pastor
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile.,Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Andrea Gonzalez
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile
| | - Nicolás Ramos-Escobar
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile
| | - Edgar Pastene
- Departamento de Farmacia, Universidad de Concepción, Concepción, Chile
| | - Leonel E Rojo
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Ricardo B Maccioni
- International Center for Biomedicine (ICC), Santiago, Chile.,Laboratory of Neurosciences and Functional Medicine, Faculty of Sciences, University of Chile, Santiago, Chile
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13
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Yang CC, Luo Y, Guo KW, Zheng CC, Li L, Zhang L. Cornel Iridoid Glycoside Regulates Modification of Tau and Alleviates Synaptic Abnormalities in Aged P301S Mice. Curr Med Sci 2021; 40:1040-1046. [PMID: 33428131 DOI: 10.1007/s11596-020-2285-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/09/2020] [Indexed: 10/22/2022]
Abstract
Alzheimer's disease (AD), also defined as a tauopathology, is a common neurodegenerative disease. Hyper-phosphorylation, cleavage or truncation, and aggregation of tau contribute to AD. Thus, targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD. This study understood how cornel iridoid glycoside (CIG) affects tau post-translational modifications and synaptic abnormalities. The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month. Hyperphosphorylated and truncated tau, synapse-associated proteins and glutamatergic receptors were all detected using Western blotting. The interactions between Morroniside (MOR) or Loganin (LOG) and tau were detected using Autodock and Surface Plasmon Resonance (SPR). The effects of CIG on the aggregation of tau were investigated using a cell-free system. CIG attenuated tau hyperphosphorylation at Thr205, Ser212, Ser262, Thr231 and Ser235 (AT180), but had no effect on tau truncation in the brains of 10-month old P301S mice. Binding free energies and interactions revealed that MOR and LOG bound with tau. We also found that CIG upregulated synapse-associated proteins such as PSD-95, syntaxin1A and synaptotagmin. In addition, CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels. CIG improves post-translational modification of tau as well as synaptic abnormalities. The data presented here reveal that CIG may be used in the treatment of AD.
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Affiliation(s)
- Cui-Cui Yang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China
| | - Yi Luo
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China
| | - Kai-Wen Guo
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China
| | - Ceng-Ceng Zheng
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China
| | - Lin Li
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China.
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14
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Niewiadomska G, Niewiadomski W, Steczkowska M, Gasiorowska A. Tau Oligomers Neurotoxicity. Life (Basel) 2021; 11:28. [PMID: 33418848 PMCID: PMC7824853 DOI: 10.3390/life11010028] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer's disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other's aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system.
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Affiliation(s)
- Grazyna Niewiadomska
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Wiktor Niewiadomski
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland; (W.N.); (M.S.); (A.G.)
| | - Marta Steczkowska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland; (W.N.); (M.S.); (A.G.)
| | - Anna Gasiorowska
- Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland; (W.N.); (M.S.); (A.G.)
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15
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Lo CH, Sachs JN. The role of wild-type tau in Alzheimer's disease and related tauopathies. JOURNAL OF LIFE SCIENCES (WESTLAKE VILLAGE, CALIF.) 2020; 2:1-17. [PMID: 33665646 PMCID: PMC7929479 DOI: 10.36069/jols/20201201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Tau oligomers have recently emerged as the principal toxic species in Alzheimer's disease (AD) and tauopathies. Tau oligomers are spontaneously self-assembled soluble tau proteins that are formed prior to fibrils, and they have been shown to play a central role in neuronal cell death and in the induction of neurodegeneration in animal models. As the therapeutic paradigm shifts to targeting toxic tau oligomers, this suggests the focus to study tau oligomerization in species that are less susceptible to fibrillization. While truncated and mutation containing tau as well as the isolated repeat domains are particularly prone to fibrillization, the wild-type (WT) tau proteins have been shown to be resistant to fibril formation in the absence of aggregation inducers. In this review, we will summarize and discuss the toxicity of WT tau both in vitro and in vivo, as well as its involvement in tau oligomerization and cell-to-cell propagation of pathology. Understanding the role of WT tau will enable more effective biomarker development and therapeutic discovery for treatment of AD and tauopathies.
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Affiliation(s)
- Chih Hung Lo
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
- Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
| | - Jonathan N. Sachs
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
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16
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Geissoschizoline, a promising alkaloid for Alzheimer's disease: Inhibition of human cholinesterases, anti-inflammatory effects and molecular docking. Bioorg Chem 2020; 104:104215. [PMID: 32920358 DOI: 10.1016/j.bioorg.2020.104215] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/30/2020] [Accepted: 08/04/2020] [Indexed: 12/29/2022]
Abstract
Due to the lack of effective pharmacotherapy options to treats Alzheimer's disease, new strategies have been approached in the search for multi-target molecules as therapeutic options. In this work, four indole alkaloids, geissoschizoline, geissoschizone, geissospermine, and 3',4',5',6'-tetradehydrogeissospermine were isolated from Geissospermum vellosii (Pao pereira) and evaluated for their anticholinesterase activities. While geissospermine inhibited only butyrylcholinesterase (BChE), the other alkaloids behaved as non-selective inhibitors of acetylcholinesterase (AChE) and BChE. In cell viability tests, only geissoschizoline was not cytotoxic. Therefore, geissoschizoline actions were also evaluated in human cholinesterases, where it was twice as potent inhibitor of hBChE (IC50 = 10.21 ± 0.01 µM) than hAChE (IC50 = 20.40 ± 0.93 µM). On enzyme kinetic studies, geissoschizoline presented a mixed-type inhibition mechanism for both enzymes. Molecular docking studies pointed interactions of geissoschizoline with active site and peripheral anionic site of hAChE and hBChE, indicating a dual site inhibitor profile. Moreover, geissoschizoline also played a promising anti-inflammatory role, reducing microglial release of NO and TNF-α at a concentration (1 μM) ten and twenty times lower than the IC50 values of hBChE and hAChE inhibition, respectively. These actions give geissoschizoline a strong neuroprotective character. In addition, the ability to inhibit hAChE and hBChE, with approximate inhibitory potencies, accredits this alkaloid for therapeutic use in the moderate to severe phase of AD. Thus, geissoschizoline emerges as a possible multi-target prototype that can be very useful in preventing neurodegeneration and restore neurotransmission.
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17
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González A, Guzmán-Martínez L, Maccioni RB. Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer's Disease. J Alzheimers Dis 2020; 77:877-883. [PMID: 32741827 DOI: 10.3233/jad-200386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND A major drawback in Alzheimer's disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. OBJECTIVE To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. METHODS We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody. RESULTS The HMW/LMWtau ratio was statistically different between AD patients and controls. CONCLUSIONS Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.
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Affiliation(s)
- Andrea González
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Leonardo Guzmán-Martínez
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile.,Department of Neurology, Faculty of Medicine, University of Chile, Santiago, Chile
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18
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Dominguez-Meijide A, Vasili E, König A, Cima-Omori MS, Ibáñez de Opakua A, Leonov A, Ryazanov S, Zweckstetter M, Griesinger C, Outeiro TF. Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization. Sci Rep 2020; 10:12827. [PMID: 32732936 PMCID: PMC7393090 DOI: 10.1038/s41598-020-69744-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 07/08/2020] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.
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Affiliation(s)
- Antonio Dominguez-Meijide
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany.,Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Eftychia Vasili
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
| | - Annekatrin König
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany
| | - Maria-Sol Cima-Omori
- German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany
| | - Alain Ibáñez de Opakua
- German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany
| | - Andrei Leonov
- Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany
| | - Sergey Ryazanov
- Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany
| | - Markus Zweckstetter
- German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.,Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.,Department of Neurology, University Medical Center Göttingen, University of Göttingen, Waldweg 33, 37073, Göttingen, Germany
| | - Christian Griesinger
- Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany
| | - Tiago F Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, 37073, Göttingen, Germany. .,Max Planck Institute for Experimental Medicine, Göttingen, Germany. .,Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
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19
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Zanon VS, Lima JA, Amaral RF, Lima FRS, Kitagawa DAS, França TCC, Vargas MD. Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer’s disease. J Biomol Struct Dyn 2020; 39:6112-6125. [DOI: 10.1080/07391102.2020.1796796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Vanessa S. Zanon
- Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil
| | - Josélia A. Lima
- Programa de Pós-graduação em Saúde do Adulto, Universidade Federal do Maranhão, São Luís, MA, Brazil
- Laboratório de Modelagem Aplicada a Defesa Química e Biológica (LMDQB), Instituto Militar de Engenharia, Rio de Janeiro, RJ, Brasil
| | - Rackele F. Amaral
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Flavia R. S. Lima
- Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Daniel A. S. Kitagawa
- Laboratório de Modelagem Aplicada a Defesa Química e Biológica (LMDQB), Instituto Militar de Engenharia, Rio de Janeiro, RJ, Brasil
| | - Tanos C. C. França
- Laboratório de Modelagem Aplicada a Defesa Química e Biológica (LMDQB), Instituto Militar de Engenharia, Rio de Janeiro, RJ, Brasil
| | - Maria D. Vargas
- Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil
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20
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Imam DM, Youssef MA, Attallah MF. Promising framework of nanocomposite materials: synthesis and radio-lanthanides labeling for nuclear medicine application. J Radioanal Nucl Chem 2020. [DOI: 10.1007/s10967-019-07006-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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21
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Lo CH, Lim CKW, Ding Z, Wickramasinghe SP, Braun AR, Ashe KH, Rhoades E, Thomas DD, Sachs JN. Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies. Alzheimers Dement 2019; 15:1489-1502. [PMID: 31653529 DOI: 10.1016/j.jalz.2019.06.4954] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/30/2019] [Accepted: 06/19/2019] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Understanding the heterogeneous pathology in Alzheimer's disease and related tauopathies is one of the most urgent and fundamental challenges facing the discovery of novel disease-modifying therapies. Through monitoring ensembles of toxic and nontoxic tau oligomers spontaneously formed in cells, our biosensor technology can identify tool compounds that modulate tau oligomer structure and toxicity, providing much needed insight into the nature and properties of toxic tau oligomers. BACKGROUND Tauopathies are a group of neurodegenerative disorders characterized by pathologic aggregation of the microtubule binding protein tau. Recent studies suggest that tau oligomers are the primary toxic species in tauopathies. NEW/UPDATED HYPOTHESIS We hypothesize that tau biosensors capable of monitoring tau oligomer conformation are able to identify tool compounds that modulate the structure and conformation of these tau assemblies, providing key insight into the unique structural fingerprints of toxic tau oligomers. These fingerprints will provide gravely needed biomarker profiles to improve staging of early tauopathy pathology and generate lead compounds for potential new therapeutics. Our time-resolved fluorescence resonance energy transfer biosensors provide us an exquisitely sensitive technique to monitor minute structural changes in monomer and oligomer conformation. In this proof-of-concept study, we identified a novel tool compound, MK-886, which directly binds tau, perturbs the conformation of toxic tau oligomers, and rescues tau-induced cytotoxicity. Furthermore, we show that MK-886 alters the conformation of tau monomer at the proline-rich and microtubule binding regions, stabilizing an on-pathway oligomer. MAJOR CHALLENGES FOR THE HYPOTHESIS Our approach monitors changes in the ensemble of assemblies that are spontaneously formed in cells but does not specifically isolate or enrich unique toxic tau species. However, time-resolved fluorescence resonance energy transfer does not provide high-resolution, atomic scale information, requiring additional experimental techniques to resolve the structural features stabilized by different tool compounds. LINKAGE TO OTHER MAJOR THEORIES Our biosensor technology is broadly applicable to other areas of tauopathy therapeutic development. These biosensors can be readily modified for different isoforms of tau, specific post-translational modifications, and familial Alzheimer's disease-associated mutations. We are eager to explore tau interactions with chaperone proteins, monitor cross-reactivity with other intrinsically disordered proteins, and target seeded oligomer pathology.
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Affiliation(s)
- Chih Hung Lo
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Colin Kin-Wye Lim
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Zhipeng Ding
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Sanjula P Wickramasinghe
- Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Anthony R Braun
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Karen H Ashe
- Department of Neurology, University of Minnesota, Minneapolis, MN, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN, USA; Geriatric Research, Education, and Clinical Centers, Veterans Affairs Medical Center, Minneapolis, MN, USA
| | - Elizabeth Rhoades
- Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USA; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA
| | - David D Thomas
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA; Photonic Pharma LLC, Minneapolis, MN, USA
| | - Jonathan N Sachs
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.
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22
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Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N. Neuroinflammation as a Common Feature of Neurodegenerative Disorders. Front Pharmacol 2019; 10:1008. [PMID: 31572186 PMCID: PMC6751310 DOI: 10.3389/fphar.2019.01008] [Citation(s) in RCA: 489] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 08/08/2019] [Indexed: 12/26/2022] Open
Abstract
Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of β-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer’s disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson’s disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer’s disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.
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Affiliation(s)
- Leonardo Guzman-Martinez
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile.,Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Víctor Andrade
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile
| | - Leonardo Patricio Navarrete
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile
| | - María Gabriela Pastor
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile.,Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Nicolas Ramos-Escobar
- Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile
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23
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Panchal K, Tiwari AK. Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion 2019; 47:151-173. [PMID: 30408594 DOI: 10.1016/j.mito.2018.11.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 10/08/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022]
Abstract
Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.
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Affiliation(s)
- Komal Panchal
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India
| | - Anand Krishna Tiwari
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India.
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24
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Kim H, Lee JU, Kim S, Song S, Sim SJ. A Nanoplasmonic Biosensor for Ultrasensitive Detection of Alzheimer's Disease Biomarker Using a Chaotropic Agent. ACS Sens 2019; 4:595-602. [PMID: 30747516 DOI: 10.1021/acssensors.8b01242] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Blood-based diagnosis (hemodiagnosis) of Alzheimer's disease (AD) is emerging as a promising alternative to cerebrospinal-fluid-based methods because blood contains various kinds of AD biomarkers, including amyloid beta 1-40, 1-42, and τ (tau) protein. However, with current technology, the accuracy of the blood-plasma-based methods is relatively low compared to the traditional methods because the concentration of AD biomarkers in blood plasma is incredibly low, and diverse interference is present in blood plasma, which hinders precise detection. Here, we suggest a nanoplasmonic biosensor using gold nanorods with a chaotropic agent for precise ultrasensitive detecting of Alzheimer's disease biomarkers in human plasma. This nanoplasmonic biosensor is based on the localized surface plasmon resonance (LSPR), which is extremely sensitive to the point where it can respond to an insignificant change of the refractive index around the gold nanoparticles. Also, using guanidine hydrochloride as a chaotropic agent, we can overcome the obstacles of blood-based AD diagnostics. In more detail, this agent interrupts the network between water molecules and weakens the hydrophobic interactions between proteins, remarkably improving detection capabilities to target τ protein. By reducing the overlapping ranges between protein levels in an age-matched control and AD patients' plasma, this system can accurately diagnose AD patients. This platform also can analyze disease from mild cognitive impairment using standardized blood biomarker tau protein, which is related to Alzheimer's disease. As a result, our platform can be applied to clinical trials, and thus it has excellent potential in the medical field.
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Affiliation(s)
- Hanbi Kim
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, South Korea
| | - Jong Uk Lee
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, South Korea
| | - Soohyun Kim
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, South Korea
| | - Sojin Song
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, South Korea
| | - Sang Jun Sim
- Department of Chemical and Biological Engineering, Korea University, Seoul 02841, South Korea
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25
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Mishra T, Dhaliwal HS, Singh K, Singh N. Shilajit (Mumie): Current Status of Biochemical, Therapeutic and Clinical Advances. CURRENT NUTRITION & FOOD SCIENCE 2019. [DOI: 10.2174/1573401313666170823160217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background: Shilajit (mumie), a natural multi-component herbomineral ethnomedicinal
food, is used as a traditional medicine for enhancing the quality of life and for management of health
ailments in many countries of the world. Use of Shilajit as an adaptogen, aphrodisiac, rejuvenator and
anti-aging substance is mentioned in many ancient texts. This review aims to provide comprehensive
insights into its biochemical aspects, microbial role in biosynthesis, bioactivities and to establish correlation
between traditional uses and scientifically validated research findings.
Methods:
Scientific literature and ethnopharmacological information were compiled from the published
peer-reviewed articles, unpublished materials, thesis, books, patent databases, clinical trial registries
and from the websites of research councils of traditional medicine. The scientific databases,
thesis repositories and books databases were searched with keywords Shilajit, mumie, mumijo,
salajeet, asphaltum, fulvic acid, dibenzo-alpha-pyrones etc.
Results:
Scientifically validated research and ancient texts suggest multifaceted benefits of Shilajit. It
is endowed with anti-stress, memory and energy enhancing, antioxidant, anti-inflammatory, antidiabetic,
spermatogenic, neuroprotective, antiulcer and wound healing activities. These pharmacological
effects are mainly attributed to the presence of humic acid, fulvic acid, dibenzo-α-pyrones, dibenzo-
α-pyrones chromoproteins and trace elements.
Conclusion:
This review summarizes the traditional importance of Shilajit for the treatment and prevention
of several acute and chronic diseases and health ailments. Despite numerous health claims,
there are still major gaps in our understanding of its mechanism of action, variability in efficacy and
toxicity profile. Therefore, a coordinated interdisciplinary approach is needed to establish the underlying
mechanisms of action, comprehensive toxicological profile, pharmacokinetics parameters and effects
on different organ systems. Regulatory and governmental impetus to basic and clinical research,
safety testing and formulations quality control is warranted.
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Affiliation(s)
- Tanuja Mishra
- Department of Biotechnology, Eternal University, Baru Sahib-173101, Himachal Pradesh, India
| | - Harcharan S. Dhaliwal
- Department of Biotechnology, Eternal University, Baru Sahib-173101, Himachal Pradesh, India
| | - Karan Singh
- Chemistry, Eternal University, Baru Sahib-173101, Himachal Pradesh, India
| | - Nasib Singh
- Department of Biotechnology, Eternal University, Baru Sahib-173101, Himachal Pradesh, India
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26
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Guzmán-Martínez L, Tapia JP, Farías GA, González A, Estrella M, Maccioni RB. The Alz-tau Biomarker for Alzheimer's Disease: Study in a Caucasian Population. J Alzheimers Dis 2019; 67:1181-1186. [PMID: 30775977 DOI: 10.3233/jad-180637] [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] [Indexed: 01/23/2023]
Abstract
The establishment of a molecular biomarker for early detection of Alzheimer's disease (AD) is critical for diagnosis and follow up of patients, and as a quantitative parameter in the evaluation of potential new drugs to control AD. A list of blood biomarkers has been reported but none has been validated for the Alzheimer's clinic. The changes in hyperphosphorylated tau and amyloid peptide in the cerebrospinal fluid is currently used as a tool in the clinics and for research purposes, but this method is highly invasive. Recently, we reported a non-invasive and reliable blood biomarker that correlates the increase in the ratio of heavy tau (HMWtau) and the low molecular weight tau (LMWtau) in human platelets and the decrease in the brain volume as measured by structural MRI. This molecular marker has been named Alz-tau®. Beyond the clinical trials developed with a Latin American population, the present study focuses on an evaluation of this biomarker in a Caucasian population. We examined 36 AD patients and 15 cognitively normal subjects recruited in Barcelona, Spain. Tau levels in platelets were determined by immunoreactivity and the cognitive status by using GDS and MMSE neuropsychological tests. The HMW/LMW tau ratio was statistically different between controls and AD patients. A high correlation was found between the increase in MMSE scores and HMW/LMW tau ratio. This study showed that this ratio is significantly higher in AD patients than controls. Moreover, this study on a peripheral marker of AD is valuable to understanding the AD pathogenesis.
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Affiliation(s)
- Leonardo Guzmán-Martínez
- Laboratory of Neuroscience, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - José Pablo Tapia
- Laboratory of Neuroscience, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Gonzalo A Farías
- Department of Neurology, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Andrea González
- Laboratory of Neuroscience, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Matías Estrella
- Laboratory of Neuroscience, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile
| | - Ricardo B Maccioni
- Laboratory of Neuroscience, International Center for Biomedicine (ICC) and Faculty of Sciences, University of Chile, Santiago, Chile.,Department of Neurology, Faculty of Medicine, University of Chile, Santiago, Chile
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27
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Lima JA, Hamerski L. Alkaloids as Potential Multi-Target Drugs to Treat Alzheimer's Disease. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2019. [DOI: 10.1016/b978-0-444-64183-0.00008-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
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28
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Bachmann MF, Jennings GT, Vogel M. A vaccine against Alzheimer`s disease: anything left but faith? Expert Opin Biol Ther 2018; 19:73-78. [DOI: 10.1080/14712598.2019.1554646] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Martin F. Bachmann
- RIA Immunology, Department of BioMedical Research, University of Bern, Bern,
Switzerland
- The Jenner Institute, Nuffield Department of Medicine, The Henry Wellcome Building for Molecular Physiology, University of Oxford,
Oxford, UK
| | - Gary T Jennings
- Hypopet AG, Zürich,
Switzerland
- Saiba GmbH, Pfäffikon,
Switzerland
| | - Monique Vogel
- RIA Immunology, Department of BioMedical Research, University of Bern, Bern,
Switzerland
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29
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Kurochkina N, Bhaskar M, Yadav SP, Pant HC. Phosphorylation, Dephosphorylation, and Multiprotein Assemblies Regulate Dynamic Behavior of Neuronal Cytoskeleton: A Mini-Review. Front Mol Neurosci 2018; 11:373. [PMID: 30349458 PMCID: PMC6186834 DOI: 10.3389/fnmol.2018.00373] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 09/20/2018] [Indexed: 12/28/2022] Open
Abstract
Cellular localization, assembly and abnormal aggregation of neurofilaments depend on phosphorylation. Pathological processes associated with neurodegeneration exhibit aberrant accumulation of microtubule associated aggregated forms of hyperphosphorylated neuronal protein tau in cell bodies. These processes are critical for the disease progression in patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. In healthy cells, tau is localized in axons. Topographic regulation suggests that whereas the sites of synthesis of kinases and neurofilaments are the cell bodies, and sites of their functional assemblies are axons, phosphorylation/dephosphorylation are the key processes that arrange the molecules at their precise locations. Phosphorylation sites in the dynamic developmental and degenerative processes differ. Not all these processes are well understood. New advancements identify epigenetic factors involved in AD which account for the influence of age-related environment/genome interactions leading to the disease. Progress in proteomics highlights previously found major proteins and adds more to the list of those involved in AD. New key elements of specificity provide determinants of molecular recognition important for the assembly of macromolecular complexes. In this review, we discuss aberrant spatial distribution of neuronal polypeptides observed in neuropathies: aggregation, association with proteins of the neuronal cytoskeleton, and phosphorylation dependent dynamics. Particularly, we emphasize recent advancements in understanding the function and determinants of specific association of molecules involved in Alzheimer's disease with respect to the topographic regulation of phosphorylation in neuronal cytoskeleton and implications for the design of new therapies. Further, we address the role of various filament systems in maintenance of the shape, rigidity and dynamics of the cytoskeleton.
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Affiliation(s)
- Natalya Kurochkina
- Department of Biophysics, The School of Theoretical Modeling, Washington, DC, United States
| | - Manju Bhaskar
- Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Sharda Prasad Yadav
- Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Harish C. Pant
- Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
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30
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Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration. Int J Mol Sci 2018; 19:ijms19040956. [PMID: 29570615 PMCID: PMC5979395 DOI: 10.3390/ijms19040956] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/05/2018] [Accepted: 03/08/2018] [Indexed: 12/15/2022] Open
Abstract
Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies. According to evidence from a series of studies, these changes generate a feedback mechanism reactivating microglia and provoking constant cellular damage. Thus, the previously summarized mechanisms could explain the onset and progression of different tauopathies and their functional/behavioral effects, opening the window towards an understanding of the molecular basis of anomalous tau interactions. Despite clinical and pathological differences, increasing experimental evidence indicates an overlap between tauopathies and synucleinopathies, considering that neuroinflammatory events are involved and the existence of protein misfolding. Neurofibrillary tangles of pathological tau (NFT) and Lewy bodies appear to coexist in certain brain areas. Thus, the co-occurrence of synucleinopathies with tauopathies is evidenced by several investigations, in which NFT were found in the substantia nigra of patients with Parkinson’s disease, suggesting that the pathologies share some common features at the level of neuroinflammatory events.
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31
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Habtemariam S. Molecular Pharmacology of Rosmarinic and Salvianolic Acids: Potential Seeds for Alzheimer's and Vascular Dementia Drugs. Int J Mol Sci 2018; 19:E458. [PMID: 29401682 PMCID: PMC5855680 DOI: 10.3390/ijms19020458] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 12/20/2022] Open
Abstract
Both caffeic acid and 3,4-dihydroxyphenyllactic acid (danshensu) are synthesized through two distinct routs of the shikimic acid biosynthesis pathway. In many plants, especially the rosemary and sage family of Lamiaceae, these two compounds are joined through an ester linkage to form rosmarinic acid (RA). A further structural diversity of RA derivatives in some plants such as Salvia miltiorrhiza Bunge is a form of RA dimer, salvianolic acid-B (SA-B), that further give rise to diverse salvianolic acid derivatives. This review provides a comprehensive perspective on the chemistry and pharmacology of these compounds related to their potential therapeutic applications to dementia. The two common causes of dementia, Alzheimer's disease (AD) and stroke, are employed to scrutinize the effects of these compounds in vitro and in animal models of dementia. Key pharmacological mechanisms beyond the common antioxidant and anti-inflammatory effects of polyphenols are highlighted with emphasis given to amyloid beta (Aβ) pathologies among others and neuronal regeneration from stem cells.
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Affiliation(s)
- Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK.
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32
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Habtemariam S. Iridoids and Other Monoterpenes in the Alzheimer's Brain: Recent Development and Future Prospects. Molecules 2018; 23:molecules23010117. [PMID: 29316661 PMCID: PMC6017424 DOI: 10.3390/molecules23010117] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 01/04/2018] [Accepted: 01/05/2018] [Indexed: 12/14/2022] Open
Abstract
Iridoids are a class of monoterpenoid compounds constructed from 10-carbon skeleton of isoprene building units. These compounds in their aglycones and glycosylated forms exist in nature to contribute to mechanisms related to plant defenses and diverse plant-animal interactions. Recent studies have also shown that iridoids and other structurally related monoterpenes display a vast array of pharmacological effects that make them potential modulators of the Alzheimer’s disease (AD). This review critically evaluates the therapeutic potential of these natural products by assessing key in vitro and in vivo data published in the scientific literature. Mechanistic approach of scrutiny addressing their effects in the Alzheimer’s brain including the τ-protein phosphorylation signaling, amyloid beta (Aβ) formation, aggregation, toxicity and clearance along with various effects from antioxidant to antiinflammatory mechanisms are discussed. The drug likeness of these compounds and future prospects to consider in their development as potential leads are addressed.
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Affiliation(s)
- Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK.
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33
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Ochalek A, Mihalik B, Avci HX, Chandrasekaran A, Téglási A, Bock I, Giudice ML, Táncos Z, Molnár K, László L, Nielsen JE, Holst B, Freude K, Hyttel P, Kobolák J, Dinnyés A. Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. ALZHEIMERS RESEARCH & THERAPY 2017; 9:90. [PMID: 29191219 PMCID: PMC5709977 DOI: 10.1186/s13195-017-0317-z] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 10/27/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. METHODS We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer's disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer's disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods. RESULTS Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-β 1-40 (Aβ1-40) and amyloid-β 1-42 (Aβ1-42). However, significantly increased Aβ1-42/Aβ1-40 ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 β, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons. CONCLUSIONS On the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aβ1-40 levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions.
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Affiliation(s)
- Anna Ochalek
- Molecular Animal Biotechnology Laboratory, Szent István University, H-2100, Gödöllő, Hungary.,BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - Balázs Mihalik
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - Hasan X Avci
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary.,Department of Anatomy, Embryology and Histology, Faculty of Medicine, University of Szeged, H-6700, Szeged, Hungary.,Present address: University Department of Otolaryngology, Head and Neck Surgery, University of Tübingen, 72076, Tübingen, Germany
| | | | | | - István Bock
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - Maria Lo Giudice
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - Zsuzsanna Táncos
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - Kinga Molnár
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, H-1117, Budapest, Hungary
| | - Lajos László
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, H-1117, Budapest, Hungary
| | - Jørgen E Nielsen
- Neurogenetics Clinic & Research Laboratory, Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Kristine Freude
- Department of Veterinary and Animal Sciences, University of Copenhagen, 1870, Copenhagen, Denmark
| | - Poul Hyttel
- Department of Veterinary and Animal Sciences, University of Copenhagen, 1870, Copenhagen, Denmark
| | - Julianna Kobolák
- BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary
| | - András Dinnyés
- Molecular Animal Biotechnology Laboratory, Szent István University, H-2100, Gödöllő, Hungary. .,BioTalentum Ltd., Aulich Lajos Street 26, H-2100, Gödöllő, Hungary.
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Ruan Q, D'Onofrio G, Sancarlo D, Greco A, Lozupone M, Seripa D, Panza F, Yu Z. Emerging biomarkers and screening for cognitive frailty. Aging Clin Exp Res 2017; 29:1075-1086. [PMID: 28260159 DOI: 10.1007/s40520-017-0741-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 02/16/2017] [Indexed: 11/24/2022]
Abstract
Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer's disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging-Alzheimer's Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.
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Affiliation(s)
- Qingwei Ruan
- Shanghai Key Laboratory of Clinical Geriatrics, Department of Geriatrics, Huadong Hospital, and Research Center of Aging and Medicine, Shanghai Institute of Geriatrics and Gerontology, Shanghai Medical College, Fudan University, Shanghai, 200040, China
| | - Grazia D'Onofrio
- Geriatric Unit and Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy
| | - Daniele Sancarlo
- Geriatric Unit and Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy
| | - Antonio Greco
- Geriatric Unit and Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy
| | - Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Davide Seripa
- Geriatric Unit and Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy
| | - Francesco Panza
- Geriatric Unit and Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
- Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.
| | - Zhuowei Yu
- Shanghai Key Laboratory of Clinical Geriatrics, Department of Geriatrics, Huadong Hospital, and Research Center of Aging and Medicine, Shanghai Institute of Geriatrics and Gerontology, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
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Sengupta U, Portelius E, Hansson O, Farmer K, Castillo‐Carranza D, Woltjer R, Zetterberg H, Galasko D, Blennow K, Kayed R. Tau oligomers in cerebrospinal fluid in Alzheimer's disease. Ann Clin Transl Neurol 2017; 4:226-235. [PMID: 28382304 PMCID: PMC5376754 DOI: 10.1002/acn3.382] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/26/2016] [Accepted: 11/18/2016] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE With an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD. METHODS A multicentric collaborative study involving a double-blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls. RESULTS Using a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age-matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls. CONCLUSION These assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.
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Affiliation(s)
- Urmi Sengupta
- Mitchell Center for Neurodegenerative DiseasesUniversity of Texas Medical BranchGalvestonTexas
- Department of Neurology, and Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonTexas
| | - Erik Portelius
- Clinical Neurochemistry LaboratoryInstitute of Neuroscience and Physiologythe Sahlgrenska Academy at University of GothenburgMölndalSweden
| | - Oskar Hansson
- Clinical Memory Research UnitDepartment of Clinical SciencesLund UniversityLundSweden
- Memory ClinicSkåne University HospitalLund Sweden
| | - Kathleen Farmer
- Mitchell Center for Neurodegenerative DiseasesUniversity of Texas Medical BranchGalvestonTexas
- Department of Neurology, and Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonTexas
| | - Diana Castillo‐Carranza
- Mitchell Center for Neurodegenerative DiseasesUniversity of Texas Medical BranchGalvestonTexas
- Department of Neurology, and Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonTexas
| | - Randall Woltjer
- Department of Department of PathologyOregon Health & Science UniversityPortlandOregon
| | - Henrik Zetterberg
- Clinical Neurochemistry LaboratoryInstitute of Neuroscience and Physiologythe Sahlgrenska Academy at University of GothenburgMölndalSweden
- Department of Molecular NeuroscienceUCL Institute of NeurologyQueen SquareLondonWC1N 3BGUnited Kingdom
| | - Douglas Galasko
- Department of NeuroscienceUniversity of California San DiegoSan DiagoCalifornia
| | - Kaj Blennow
- Clinical Neurochemistry LaboratoryInstitute of Neuroscience and Physiologythe Sahlgrenska Academy at University of GothenburgMölndalSweden
| | - Rakez Kayed
- Mitchell Center for Neurodegenerative DiseasesUniversity of Texas Medical BranchGalvestonTexas
- Department of Neurology, and Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonTexas
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Hensley K, Kursula P. Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer's Disease: Comparison and Contrast with Microtubule-Associated Protein Tau. J Alzheimers Dis 2017; 53:1-14. [PMID: 27079722 PMCID: PMC4942723 DOI: 10.3233/jad-160076] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alzheimer’s disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.
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Affiliation(s)
- Kenneth Hensley
- Department of Pathology, University of Toledo Health Science Campus, Toledo, OH, USA
| | - Petri Kursula
- Department of Biomedicine, University of Bergen, Bergen, Norway
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Mokhtari F, Riazi G, Balalaie S, Khodarahmi R, Karima S, Hemati A, Bolouri B, Katouli FH, Fathi E. Peptides NAP and SAL attenuate human tau granular-shaped oligomers in vitro and in SH-SY5Y cells. Neuropeptides 2016; 59:21-31. [PMID: 27461951 DOI: 10.1016/j.npep.2016.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/29/2016] [Accepted: 06/26/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Farzad Mokhtari
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, P.O. Box 131451348, Iran
| | - Gholamhossein Riazi
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, P.O. Box 131451348, Iran.
| | - Saeed Balalaie
- Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, P.O. Box 158754416, Iran; Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, P.O. Box 6734667149, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, P.O. Box 6734667149, Iran
| | - Saeed Karima
- Clinical Biochemistry Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, P.O. Box 1985717434, Iran
| | - Azam Hemati
- Monoclonal Antibody Research Center, Avicenna Research Institute (ACECR), Tehran, P.O. Box 193954741, Iran
| | - Bahram Bolouri
- Department of Biophysics and Medical Physics, Iran University of Medical Sciences, Tehran, P.O. Box 1449614525, Iran
| | - Fatemeh Hedayati Katouli
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, P.O. Box 131451348, Iran
| | - Esmat Fathi
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, P.O. Box 131451348, Iran
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38
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Kanaan NM, Cox K, Alvarez VE, Stein TD, Poncil S, McKee AC. Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy. J Neuropathol Exp Neurol 2016; 75:19-34. [PMID: 26671985 DOI: 10.1093/jnen/nlv001] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). Additionally, phosphorylation at serine 422 in tau occurs early and correlates with cognitive decline in patients with Alzheimer disease (AD). We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. Notably, the TauC3 epitope, which is abundant in AD, was relatively sparse in CTE. Together, these results provide the first description of PAD exposure, TOC1 reactive oligomers, phosphorylation of S422, and TauC3 truncation in the tau pathology of CTE.
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Kim JH, Kim E, Choi WH, Lee J, Lee JH, Lee H, Kim DE, Suh YH, Lee MJ. Inhibitory RNA Aptamers of Tau Oligomerization and Their Neuroprotective Roles against Proteotoxic Stress. Mol Pharm 2016; 13:2039-48. [PMID: 27120117 DOI: 10.1021/acs.molpharmaceut.6b00165] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tau is a cytosolic protein that functions in the assembly and stabilization of axonal microtubule networks. Its oligomerization may be the rate-limiting step of insoluble aggregate formation, which is a neuropathological hallmark of Alzheimer's disease (AD) and a number of other tauopathies. Recent evidence indicates that soluble tau oligomers are the toxic species for tau-mediated pathology during AD progression. Herein, we describe novel RNA aptamers that target human tau and were identified through an in vitro selection process. These aptamers significantly inhibited the oligomerization propensity of tau both in vitro and in cultured cell models of tauopathy without affecting the half-life of tau. Tauopathy model cells treated with the aptamers were less sensitized to proteotoxic stress induced by tau overexpression. Moreover, the tau aptamers significantly alleviated synthetic tau oligomer-mediated neurotoxicity and dendritic spine loss in primary hippocampal neurons. Thus, our study demonstrates that delaying tau assembly with RNA aptamers is an effective strategy for protecting cells under various neurodegenerative stresses originating from pathogenic tau oligomerization.
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Affiliation(s)
- Ji Hyeon Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.,Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea
| | - Eunkyoung Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea
| | - Won Hoon Choi
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.,Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea
| | - Jeeyoung Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.,Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea
| | - Jung Hoon Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea
| | - Hyojin Lee
- Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.,Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080, Korea
| | - Dong-Eun Kim
- Department of Bioscience and Biotechnology, Konkuk University , Seoul 05029, Korea
| | - Young Ho Suh
- Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.,Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080, Korea
| | - Min Jae Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.,Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.,Biomedical Research Institutue, Seoul National University Hospital , Seoul 03080, Korea
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40
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Ji Y, Zhang A, Chen X, Che X, Zhou K, Wang Z. Sodium humate accelerates cutaneous wound healing by activating TGF-β/Smads signaling pathway in rats. Acta Pharm Sin B 2016; 6:132-40. [PMID: 27006897 PMCID: PMC4788707 DOI: 10.1016/j.apsb.2016.01.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/03/2015] [Accepted: 11/17/2015] [Indexed: 01/06/2023] Open
Abstract
Sodium humate (HA-Na) has been topically used as a wound healing and anti-inflammatory agent in folk medicine. In the present study, HA-Na was investigated for cutaneous wound healing in Sprague-Dawley rats. HA-Na solution (1.0%, w/v) was topically administered to rats undergoing excision wound models. Healing was assessed with a recombinant bovine basic fibroblast growth factor for external use as positive control. Wound healing rates were calculated on Day 3, 6, 9, 14 and 21 after injury, and tissues were also harvested after the same intervals for histological analysis. In addition, tissue hydroxyproline levels were measured. Furthermore, mRNA levels and protein expressions of transforming growth factor-β1, 2, 3 (TGF-β1, 2, 3) were determined by RT-PCR and western blot. Protein expression levels of Smad-2, -3, -4 and -7 were also detected by western blot. Our study demonstrates that HA-Na has the capacity to promote wound healing in rats via accelerated wound contraction and increased hydroxyproline content. More importantly, these wound healing effects of HA-Na might be mediated through the TGF-β/Smad signaling pathway. HA-Na may be an effective agent for enhanced wound healing.
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Abstract
Alzheimer's disease (AD) is a neurodegenerative illness associated with dementia and is most prevalent among the elderly population. Current medications can only treat symptoms. Alkaloids are structurally diverse and have been an important source of therapeutics for various brain disorders. Two US Food and Drug Administration (FDA)-approved acetylcholinesterase inhibitors for AD, galantamine and rivastigmine, are in fact alkaloids. In addition, clinical trials of four other extensively studied alkaloids-huperzine A, caffeine, nicotine, and indomethacin-have been conducted but do not convincingly demonstrate their clinical efficacy for AD. Interestingly, rhynchophylline, a known neuroprotective alkaloid, was recently discovered by in silico screening as an inhibitor of EphA4, a novel target for AD. Here, we review the pathophysiological mechanisms underlying AD, current treatment strategies, and therapeutic potential of several selected plant alkaloids in AD, highlighting their various drug targets and the key supportive preclinical and clinical studies. Future research should include more rigorous clinical studies of the most promising alkaloids, the further development of recently discovered candidate alkaloids, and the continual search for new alkaloids for relevant drug targets. It remains promising that an alkaloid drug candidate could significantly affect the progression of AD in addition to providing symptomatic relief.
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Affiliation(s)
- Yu Pong Ng
- Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
| | - Terry Cho Tsun Or
- Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
| | - Nancy Y Ip
- Division of Life Science, Molecular Neuroscience Center, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
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Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. Altern Ther Health Med 2015; 15:61. [PMID: 25888188 PMCID: PMC4369892 DOI: 10.1186/s12906-015-0583-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 02/21/2015] [Indexed: 12/17/2022]
Abstract
Background Homocysteine and pro-inflammatory mediators such as cyclooxygenase-2 (COX-2) have been linked to vascular dysfunction and risks of cardiovascular diseases. Fulvic acid (FA), a class of compounds of humic substances, possesses various pharmacological properties. However, the effect of FA on inflammatory responses of the monocytes remains unclear. We investigated the regulatory effect of FA on homocysteine-induced COX-2 expression in human monocytes. Methods Peripheral blood monocytes and U937 cells were used for all experiments. Real-time PCR and ELISA assay were used to analyze the COX-2 mRNA expression and PGE2 secretion, respectively. Specific inhibitors were used to investigate the mechanism of homocysteine-mediating COX-2 mRNA expression and PGE2 secretion. Luciferase assay, transcription factor ELISA, and chromatin immunoprecipitation were used to determine the role of nuclear factor-κB in FA-mediated inhibition of homocysteine effect on monocytes. Results The results show that pretreating monocytes with FA inhibited the homocysteine-induced COX-2 expression in a dose-dependent manner. Stimulation of U937 monocytes with homocysteine induced rapid increases in the phosphorylation of ERK and JNK; the inhibitor for ERK and JNK attenuated the homocysteine-induced nuclear factor-κB activation and COX-2 expression. Transcription factor ELISA and chromatin immunoprecipitation assays showed that FA blocked the homocysteine-induced increases in the binding activity and in vivo promoter binding of nuclear factor-κB in monocytes. Conclusions Our findings provide a molecular mechanism by which FA inhibits homocysteine-induced COX-2 expression in monocytes, and a basis for using FA in pharmaceutical therapy against inflammation.
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Okuda M, Hijikuro I, Fujita Y, Wu X, Nakayama S, Sakata Y, Noguchi Y, Ogo M, Akasofu S, Ito Y, Soeda Y, Tsuchiya N, Tanaka N, Takahashi T, Sugimoto H. PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo. PLoS One 2015; 10:e0117511. [PMID: 25659102 PMCID: PMC4319983 DOI: 10.1371/journal.pone.0117511] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 12/29/2014] [Indexed: 12/16/2022] Open
Abstract
In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.
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MESH Headings
- Amino Acid Substitution
- Animals
- Heterocyclic Compounds, 4 or More Rings/chemical synthesis
- Heterocyclic Compounds, 4 or More Rings/chemistry
- Heterocyclic Compounds, 4 or More Rings/pharmacology
- Humans
- Indoles/chemical synthesis
- Indoles/chemistry
- Indoles/pharmacology
- Male
- Mice
- Mice, Inbred ICR
- Mice, Transgenic
- Mutation, Missense
- Protein Aggregation, Pathological/drug therapy
- Protein Aggregation, Pathological/genetics
- Protein Aggregation, Pathological/metabolism
- Protein Aggregation, Pathological/pathology
- Pyrazoles/chemical synthesis
- Pyrazoles/chemistry
- Pyrazoles/pharmacology
- Tauopathies/drug therapy
- Tauopathies/genetics
- Tauopathies/metabolism
- Tauopathies/pathology
- tau Proteins/antagonists & inhibitors
- tau Proteins/genetics
- tau Proteins/metabolism
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Affiliation(s)
- Michiaki Okuda
- Pharma Eight Co., Ltd., Kyoto, Japan
- Graduate School of Brain Science, Doshisha University, Kyoto, Japan
- * E-mail:
| | | | - Yuki Fujita
- Pharma Eight Co., Ltd., Kyoto, Japan
- Graduate School of Brain Science, Doshisha University, Kyoto, Japan
| | - Xiaofeng Wu
- Key Lab of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | | | | | | | - Makoto Ogo
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Shigeru Akasofu
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Yoshimasa Ito
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Yoshiyuki Soeda
- Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan
| | - Nobuhiko Tsuchiya
- Department of Biomolecular Engineering, Kyoto Institute of Technology, Kyoto, Japan
| | - Naoki Tanaka
- Department of Biomolecular Engineering, Kyoto Institute of Technology, Kyoto, Japan
| | - Takashi Takahashi
- Natural Product Chemistry & Pharmaceutical Research Center, Yokohama College of Pharmacy, Yokohama, Japan
| | - Hachiro Sugimoto
- Pharma Eight Co., Ltd., Kyoto, Japan
- Graduate School of Brain Science, Doshisha University, Kyoto, Japan
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Rigacci S. Olive Oil Phenols as Promising Multi-targeting Agents Against Alzheimer's Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 863:1-20. [PMID: 26092624 DOI: 10.1007/978-3-319-18365-7_1] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Amyloid diseases are characterized by the deposition of typically aggregated proteins/peptides in tissues, associated with degeneration and progressive functional impairment. Alzheimer's disease is one of the most studied neurodegenerative amyloid diseases and, in Western countries, a significant cause of dementia in the elderly. The so-called "Mediterranean diet" has been considered for long as the healthier dietary regimen, characterised by a great abundance in vegetables and fruits, extra virgin olive oil as the main source of fat, a moderate consumption of red wine and a reduced intake of proteins from red meat. Recent epidemiological studies support the efficacy of the Mediterranean diet not only against cardiovascular and cancer diseases (as previously demonstrated) but also against the cognitive decline associated with ageing, and several data are highlighting the role played by natural phenols, of which red wine and extra virgin olive oil are rich, in such context. In the meantime, studies conducted both in vivo and in vitro have started to reveal the great potential of the phenolic component of extra virgin olive oil (mainly oleuropein aglycone and oleocanthal) in counteracting amyloid aggregation and toxicity, with a particular emphasis on the pathways involved in the onset and progression of Alzheimer's disease: amyloid precursor protein processing, amyloid-beta (Aβ) peptide and tau aggregation, autophagy impairment, neuroinflammation. The aim of this review is to summarize the results of such research efforts, showing how the action of these phenols goes far beyond their renowned antioxidant activity and revealing their potential as multi-targeting agents against Alzheimer's disease.
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Affiliation(s)
- Stefania Rigacci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy,
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The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 2014; 589:77-83. [PMID: 25436420 DOI: 10.1016/j.febslet.2014.11.026] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 11/17/2014] [Accepted: 11/19/2014] [Indexed: 12/16/2022]
Abstract
The accumulation of amyloid-beta (Aβ) and tau aggregates is a pathological hallmark of Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines of evidence indicate that Aβ and tau form toxic oligomeric aggregation intermediates. Depleting such structures could thus be a powerful therapeutic strategy. We generated a fragment of tau (His-K18ΔK280) that forms stable, toxic, oligomeric tau aggregates in vitro. We show that (-)-epigallocatechin gallate (EGCG), a green tea polyphenol that was previously found to reduce Aβ aggregation, inhibits the aggregation of tau K18ΔK280 into toxic oligomers at ten- to hundred-fold substoichiometric concentrations, thereby rescuing toxicity in neuronal model cells.
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Lim S, Haque MM, Kim D, Kim DJ, Kim YK. Cell-based Models To Investigate Tau Aggregation. Comput Struct Biotechnol J 2014; 12:7-13. [PMID: 25505502 PMCID: PMC4262059 DOI: 10.1016/j.csbj.2014.09.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 09/20/2014] [Accepted: 09/24/2014] [Indexed: 12/14/2022] Open
Abstract
Accumulation of abnormal tau aggregates in neuron is an important pathological signature in multiple neurodegenerative disorders including Alzheimer's disease. Tau is a neuron specific microtubule-associated protein that regulates microtubule stability, which is critical for axonal outgrowth and synaptic plasticity. In a pathological condition, tau dissociates from microtubules and forms insoluble aggregates called neurofibrillary tangles (NFTs). The accumulation of NFTs in neuron directly correlates with microtubule dysfunction and neuronal degeneration. Due to the pathophysiological importance of tau, great efforts have been made to understand tau aggregation processes and find therapeutics to halt or reverse the processes. However, progress has been slow due to the lack of a suitable method for monitoring tau aggregation. In this mini-review, we will review the conventional methods for studying tau aggregation, and introduce recent cell-based sensor approaches that allow monitoring tau aggregation in living cells.
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Affiliation(s)
- Sungsu Lim
- Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea
| | - Md Mamunul Haque
- Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea ; Biological Chemistry, University of Science and Technology, Daejon 305-333, Republic of Korea
| | - Dohee Kim
- Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea ; Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea
| | - Dong Jin Kim
- Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea
| | - Yun Kyung Kim
- Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea
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Kumar S, Tepper K, Kaniyappan S, Biernat J, Wegmann S, Mandelkow EM, Müller DJ, Mandelkow E. Stages and conformations of the Tau repeat domain during aggregation and its effect on neuronal toxicity. J Biol Chem 2014; 289:20318-32. [PMID: 24825901 PMCID: PMC4106345 DOI: 10.1074/jbc.m114.554725] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Several neurodegenerative diseases are characterized by the aggregation and posttranslational modifications of Tau protein. Its “repeat domain” (TauRD) is mainly responsible for the aggregation properties, and oligomeric forms are thought to dominate the toxic effects of Tau. Here we investigated the conformational transitions of this domain during oligomerization and aggregation in different states of β-propensity and pseudo-phosphorylation, using several complementary imaging and spectroscopic methods. Although the repeat domain generally aggregates more readily than full-length Tau, its aggregation was greatly slowed down by phosphorylation or pseudo-phosphorylation at the KXGS motifs, concomitant with an extended phase of oligomerization. Analogous effects were observed with pro-aggregant variants of TauRD. Oligomers became most evident in the case of the pro-aggregant mutant TauRDΔK280, as monitored by atomic force microscopy, and the fluorescence lifetime of Alexa-labeled Tau (time-correlated single photon counting (TCSPC)), consistent with its pronounced toxicity in mouse models. In cell models or primary neurons, neither oligomers nor fibrils of TauRD or TauRDΔK280 had a toxic effect, as seen by assays with lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, respectively. However, oligomers of pro-aggregant TauRDΔK280 specifically caused a loss of spine density in differentiated neurons, indicating a locally restricted impairment of function.
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Affiliation(s)
- Satish Kumar
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Max Planck Institute for Neurological Research, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany, and
| | - Katharina Tepper
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Center of Advanced European Studies and Research (CAESAR), 53175 Bonn, Germany
| | - Senthilvelrajan Kaniyappan
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Max Planck Institute for Neurological Research, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany, and
| | - Jacek Biernat
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Max Planck Institute for Neurological Research, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany, and the Center of Advanced European Studies and Research (CAESAR), 53175 Bonn, Germany
| | - Susanne Wegmann
- the Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, 4058 Basel, Switzerland
| | - Eva-Maria Mandelkow
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Max Planck Institute for Neurological Research, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany, and the Center of Advanced European Studies and Research (CAESAR), 53175 Bonn, Germany
| | - Daniel J Müller
- the Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, 4058 Basel, Switzerland
| | - Eckhard Mandelkow
- From the German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany, the Max Planck Institute for Neurological Research, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany, and the Center of Advanced European Studies and Research (CAESAR), 53175 Bonn, Germany,
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48
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Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci 2014; 34:4260-72. [PMID: 24647946 DOI: 10.1523/jneurosci.3192-13.2014] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.
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Mohamet L, Miazga NJ, Ward CM. Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology. World J Stem Cells 2014; 6:239-247. [PMID: 24772250 PMCID: PMC3999781 DOI: 10.4252/wjsc.v6.i2.239] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 02/19/2014] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro. We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years.
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Sahara N, Avila J. "Tau oligomers," what we know and what we don't know. Front Neurol 2014; 5:1. [PMID: 24454306 PMCID: PMC3889107 DOI: 10.3389/fneur.2014.00001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 01/02/2014] [Indexed: 11/17/2022] Open
Affiliation(s)
- Naruhiko Sahara
- Molecular Imaging Center, National Institute of Radiological Sciences , Chiba , Japan
| | - Jesus Avila
- Centro de Biologia Molecular Severo Ochoa (CSIC-UAM) , Madrid , Spain
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