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?) 积累是 AD 的重要原因，但可能不足以导致认知功能恶化。在诊断时，A¿下游的神经毒性途径可能被证明是更好或额外的治疗靶点。我们实验室和其他实验室的最新数据表明可溶性 tau 寡聚物。我们的数据表明，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，我们的数据表明另一种多酚非瑟酮可以减少总 tau 和 pS422 单体。我们拟研究水果（草莓）中发现的 CDK5 抑制剂和 SIRT1 激活剂（非瑟酮）非瑟酮的影响，及其与姜黄素对 tau 蛋白病模型中 pTau 种类以及突触和认知缺陷的协同作用，并与新型 tau 聚集抑制剂“D-TKJ1VW”的功效进行比较。 总体设计：我们将使用与散发性AD（有或没有A¿输注）相关的人类野生型tau“huTauTg”模型来探讨非瑟酮对HSP、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种类的相对影响。 目的：目标 1，确定非瑟酮与特定 tau 聚集抑制剂在 huTauTg 小鼠中的相对功效，无论是否进行 ICV 输注 A¿。目标 2：确定 HuTau Tg 小鼠中非瑟酮和姜黄素之间的协同作用（有或没有 ICV 输注 A¿）。 假设：干预措施用于阐明候选药物（tau 物种、cdk5 或 fyn 激活、增强 HSP 反应或自噬）在纠正 tau 病中的靶点参与和重要性，包括识别某些可能有益的 tau 物种。 1. 非瑟酮会减少 tau 转基因相关的 cdk5 过度激活，但不会减少 fyn。 2. 非瑟酮减少单体和不溶性 tau，增加非磷酸化 tau 并稳定微管；然而，它不会导致寡聚物的减少，并且仅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，非瑟酮不会纠正转基因依赖性热休克反应。 4. 姜黄素（而非非瑟酮）会减少总 fyn、tau 寡聚体、CP13 ptau 向树突的重新分配以及突触和认知缺陷，但不会减少 NFT 和不溶性 tau。 5. 姜黄素而非非瑟酮会刺激 Akt 及其下游 p214 tau 或 MARK/ p262 tau。 6. Fisetin 通过 SIRT1 激活来激活巨自噬途径，而姜黄素则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 的不同致病种类，但协同作用可减少老年 htau 小鼠的认知缺陷、NFT、tau 寡聚物和不溶性 tau，并纠正 NR2B 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，包括寡聚物，但不减少预先形成的不溶性沉积物或A′诱导的缺陷，并纠正突触和认知缺陷，但不纠正HSP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 机制以及干预措施的相对功效。 潜在结果：由于非瑟酮直接抑制 CDK5、稳定微管并刺激自噬途径，但对 fyn 没有影响，而姜黄素可减少致病性 fyn 并选择性减少 tau 寡聚体，因此非瑟酮应该对 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 pTau 物种将与 NR2B/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，这些研究既是机械性的，也是转化性的，推进了可溶性有毒 tau 物种的识别和无毒物种的排除以及保护性 tau 清除途径方面的知识。目标的完成将推动该领域在展示 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方面向前发展。