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: 8333462
• 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/8333462
• 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; 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肽）积累是AD的重要原因，但可能不足以导致认知能力下降。在诊断时，可以说A？下游的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涉及可溶性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（HSP）、行为、突触和Fyn（一种与Abeta毒性有关的tau激酶）中的转基因依赖性缺陷。与姜黄素相反，我们的数据显示另一种多酚非瑟酮可以减少总tau和pS422单体。我们建议研究在水果（草莓）中发现的CDK 5抑制剂和SIRT 1激活剂（fisetin）的影响及其与姜黄素在tau蛋白病模型中对pTau种类和突触和认知缺陷的协同作用，将其功效与新型tau聚集抑制剂“D-TKJ 1VW”进行比较。 总体设计：我们将使用与散发性AD相关的人野生型tau“huTauTg”模型（有或没有A？输注）探索非瑟酮对HSP、自噬、炎症、突触蛋白、fyn、cdk 5、微管/转运和线粒体缺陷、行为、tau寡聚体和tau种类的相对影响。 目的：目的1，确定在有或没有icv输注A？的huTauTg小鼠中非瑟酮与特异性tau聚集抑制剂的相对功效。目的2：确定非瑟酮和姜黄素在huTau Tg小鼠中的协同作用（有或没有icv输注A？）。 假设：干预措施用于澄清靶接合和候选物（tau种类、cdk 5或fyn激活、增强HSP应答或自噬）在校正tau病变中的意义，包括鉴定可能有益的某些tau种类。1.非瑟酮将减少tau转基因相关的cdk 5过度激活，但不包括fyn。2.非瑟酮减少单体和不溶性的ptau，增加未磷酸化的tau，并稳定微管;然而，它不会导致减少寡聚体，只会导致突触指数的适度改善，不足以改善认知。3.与姜黄素不同，非瑟酮不能纠正转基因依赖的热休克反应。4.姜黄素而非非漆黄素将减少总fyn、tau寡聚体、CP 13 ptau向树突的再分布以及突触和认知缺陷，但非NFT和不溶性tau。5.姜黄素而不是非瑟酮将刺激Akt和下游p214 tau或MARK/ p262 tau。6.非瑟酮通过SIRT 1激活激活大自噬途径，而姜黄素增加伴侣介导的微自噬。7.生物可利用的非瑟酮和姜黄素将减少ptau的不同致病性种类，但协同作用以减少认知缺陷、NFT、tau寡聚体和不溶性tau，并纠正老年htau小鼠中的NR 2B或PSD-95受体复合物失调。8.抗聚集tau抑制剂而非对照肽减少pTau，包括寡聚体而非预形成的不溶性沉积物或A β诱导的缺陷，并纠正突触和认知缺陷而非HSP缺陷。9.具有tau特异性聚集体抑制的A <$+Tau模型将有助于描述A <$vs. tau机制和干预措施的相对功效。 潜在结果：由于非瑟酮直接抑制CDK 5，稳定微管并刺激自噬途径，但对fyn没有影响，而姜黄素减少致病性fyn并选择性减少tau寡聚体，因此非瑟酮应差异地影响tau激酶/磷酸酶平衡，pTau和聚集体。一些但不是所有的pTau种类将与NR 2B/ PSD-95受体复合物失调相关，并影响认知、突触和炎症终点。 总之，这些研究是机制性和翻译性的，推进了对可溶性毒性tau种类的鉴定和无毒种类的排除以及保护性tau清除途径的认识。目标的完成将推动该领域在证明tau聚集、突触/神经保护、炎症、自噬和HSP之间的相互关系方面向前发展。