Polyphenolic Interventions for tau Pathogenesis in Alzheimers Models

多酚干预阿尔茨海默病模型中 tau 蛋白的发病机制

• 批准号: 8597919
• 负责人: SALLY ANN FRAUTSCHY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597919
• 关键词: Acetylation; Admission activity; Age; Age-Months; Aging; Alzheimer' s Disease; Amyloid; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Binding; Bioavailable; CDK5 gene; Cannulas; Caring; Cause of Death; Clinic; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complex; Curcumin; Data; Defect; Degenerative Disorder; Dendrites; Deposition; Deterioration; Diagnosis; Diet; Dose; Drug Formulations; EP300 gene; Equilibrium; Event; Excision; Exclusion; Female; Fruit; Functional disorder; Funding; Gender; Heat shock proteins; Heat-Shock Response; Histone Deacetylase; Histones; Home environment; Human; Implant; Inflammation; Inflammatory; Infusion procedures; Intervention; Knowledge; Mediating; Memory; Methods; Microtubules; Mitochondria; Modeling; Molecular Chaperones; Mus; Neurofibrillary Tangles; Nursing Homes; Outcome; Pathogenesis; Pathology; Pathway interactions; Peptides; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Phosphotransferases; Population; Prevention; Problem Solving; Proteins; Records; Relative (related person); Risk; Rodent; Safety; Strawberries; Supplementation; Synapses; Tauopathies; Testing; Time; Tissues; Toxic effect; Transgenes; Translating; Translations; Treatment Efficacy; Veterans; abeta toxicity; aged; base; comparative efficacy; cost; cost effective; design; dimer; disability; effective intervention; feeding; fisetin; hTau Mice; improved; indexing; inhibitor/antagonist; innovation; monomer; neurotoxic; new therapeutic target; novel; oxidative damage; peptide A; pharmacophore; polyphenol; protective effect; receptor; response; success; synergism; tau Proteins; tau aggregation; tau mutation; tau-1; tau-protein kinase; therapeutic target; treatment effect; uptake

DESCRIPTION (provided by applicant): A¿ peptide (A¿) accumulation is an important cause of AD, but may not be sufficient to cause cognitive deterioration. At diagnosis, neurotoxic pathways arguably downstream of A¿ may prove better or additional therapeutic targets. Recent data from our lab and others implicate soluble tau oligomers. Our data show that curcumin selectively reduces soluble tau dimers, and transgene dependent defects in heat shock proteins (HSPs), behavior, synapses and Fyn, a tau kinase implicated in Abeta toxicity. In contrast to curcumin, our data show that another polyphenol, fisetin, can reduce total tau and pS422 monomers. We propose to study the impact of fisetin, a CDK5 inhibitor and SIRT1 activator (fisetin) found in fruits (strawberries) an its synergism with curcumin on pTau species and synaptic and cognitive deficits in a tauopathy model, comparing efficacy to a novel tau aggregation inhibitor "D-TKJ1VW". General Design: We will explore the relative impact of fisetin using a human wildtype tau "huTauTg" model relevant to sporadic AD (with or without A¿ infusion) on HSPs, autophagy, inflammation, synaptic proteins, fyn, cdk5,microtubule/ transport and mitochondria defects, behavior, tau oligomers and tau species. Objectives: Aim 1, To determine relative efficacy of fisetin versus a specific tau aggregation inhibitor in huTauTg mice with or without icv infusion of A¿. Aim 2: To determine synergism between fisetin and curcumin in huTau Tg mice (with or without icv infusion of A¿). Hypotheses: Interventions are used to clarify target engagement and significance of candidates (tau species, cdk5 or fyn activation, enhancing HSPs responses or autophagy) in correcting tauopathy, including identification of certain tau species that may be beneficial. 1. Fisetin will reduce tau transgene-associated hyperactivation of cdk5 but not fyn. 2. Fisetin reduces monomeric and insoluble ptau and increases unphosphorylated tau and stabilizes microtubules; however it does not result in reduction of oligomers, and only causes modest improvements in synaptic indices insufficient to improve cognition. 3. Unlike curcumin, fisetin wil not correct transgene-dependent heat shock responses. 4. Curcumin, but not fisetin will reduce total fyn, tau oligomers, the redistribution of CP13 ptau to dendrites as well as synaptic and cognitive deficits, but not NFT and insoluble tau. 5. Curcumin but not fisetin will stimulate Akt and downstream, p214 tau or MARK/ p262 tau. 6. Fisetin activates macroautophagic pathways via SIRT1 activation, while curcumin increases chaperone mediated microautophagy. 7. Bioavailable fisetin and curcumin will reduce different pathogenic species of ptau but act synergistically to reduce cognitive deficits, NFT, tau oligomers and insoluble tau and correct NR2B or PSD-95 receptor complex dysregulation in aged htau mice. 8. Anti-aggregation tau inhibitors but not the control peptide reduce pTau including oligomers but not pre-formed insoluble deposits or A¿ induced deficits and correct synaptic and cognitive but not HSPs defects. 9. A¿ +Tau models with tau-specific aggregate inhibition will help delineate A¿ vs. tau mechanisms and relative efficacies of the interventions. Potential Outcomes: Because fisetin directly inhibits CDK5, stabilizes microtubules and stimulates autophagic pathways, but has no effect on fyn, while curcumin reduces pathogenic fyn and selectively reduces tau oligomers, fisetin should differentially impact tau kinase/phosphatase balance, pTau and aggregates. Some but not all pTau species will correlate with NR2B/ PSD-95 receptor complex dysregulation and impact cognitive, synaptic and inflammatory endpoints. In summary, these studies are both mechanistic and translational, advancing knowledge in identification of the soluble toxic tau species and exclusion of non-toxic species, and protective tau clearance pathways. Completion of aims will move the field forward in demonstrating interrelationship between tau aggregation, synapto/neuro-protection, inflammation, autophagy and the HSPs.

描述(由申请人提供)： A肽(A)积聚是阿尔茨海默病的一个重要原因，但可能不足以导致认知能力下降。在诊断时，神经毒性通路可能被证明是更好的或额外的治疗靶点。来自我们实验室和其他实验室的最新数据表明，可溶的tau寡聚体。我们的数据显示，姜黄素选择性地减少可溶性tau二聚体，以及热休克蛋白(HSPs)、行为、突触和Fyn的转基因依赖缺陷，Fyn是一种与Abeta毒性有关的tau激酶。与姜黄素相反，我们的数据显示，另一种多酚，非瑟素，可以减少总tau和pS422单体。我们建议研究在水果(草莓)中发现的CDK5抑制剂和SIRT1激活剂菲斯汀(Fisetin)的影响及其与姜黄素的协同作用，并将其与新型tau聚集抑制剂D-TKJ1VW的疗效进行比较。 总体设计：我们将利用与散发性AD相关的人类野生型tau“huTauTg”模型(有或没有A？输注)来探索Fisetin对HSPs、自噬、炎症、突触蛋白、Fyn、CDK5、微管/运输和线粒体缺陷、行为、tau寡聚体和tau物种的相对影响。 目的：1、比较侧脑室注射A？和不注射A？对huTauTg小鼠的Tau聚集抑制作用的影响。目的：研究非瑟素和姜黄素在huTau转基因小鼠(侧脑室注射或不注入A)中的协同作用。 假设：干预措施被用来阐明靶点参与和候选基因(tau基因、CDK5或Fyn激活、增强HSPs反应或自噬)在纠正tau病方面的意义，包括识别某些可能有益的tau基因。1.非瑟丁可降低tau转基因相关的CDK5的过度激活，但不能降低Fyn的激活。2.菲斯汀降低单体和不溶性ptau，增加非磷酸化tau和稳定微管；但它并不导致寡聚体减少，仅引起不足以改善认知的突触指数的轻微改善。3.与姜黄素不同，非瑟素不会纠正转基因依赖的热休克反应。4.姜黄素能减少总Fyn、tau寡聚体、CP13ptau向树突的重新分布以及突触和认知功能障碍，但不能减少NFT和不溶性tau。5.姜黄素可刺激Akt及其下游，P214 tau或Mark/p262 tau。6.非瑟素通过激活SIRT1激活宏自噬途径，而姜黄素增加伴侣蛋白介导的微自噬。7.生物可利用的非瑟素和姜黄素可减少ptau的不同致病物种，但协同作用可减少老年htau小鼠的认知障碍、NFT、tau寡聚体和不溶性tau，并纠正NR2B或PSD-95受体复合体失调。8.抗聚集tau抑制剂而不是对照肽可减少ptau，包括寡聚体，但不能减少预先形成的不溶性沉淀物或Aβ诱导的缺陷，并纠正突触和认知缺陷，但不能纠正HSPs缺陷。9.具有tau特异性聚集抑制的A？+Tau模型将有助于描述A？与tau的机制和干预的相对有效性。 潜在结果：由于非瑟素直接抑制CDK5，稳定微管和刺激自噬途径，但对FYN没有影响，而姜黄素减少致病性FYN并选择性地减少tau寡聚体，因此Fisetin应该对tau激酶/磷酸酶平衡、ptau和聚集体产生不同的影响。一些但不是所有的ptau物种将与NR2B/PSD-95受体复合体失调相关，并影响认知、突触和炎症终点。综上所述，这些研究既是机械性的，也是转化性的，在鉴定可溶性有毒tau物种、排除无毒物种和保护tau清除途径方面促进了知识的进步。AIMS的完成将推动tau聚集、突触/神经保护、炎症、自噬和热休克蛋白之间的相互关系的研究取得进展。