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？）的积累是AD的重要原因，但可能不足以引起认知检测。在诊断方面，可以说在A检测的下游神经毒性途径可能是更好或其他治疗靶标。我们实验室和其他造成可溶性tau低聚物的最新数据。我们的数据表明，姜黄素有选择地降低固体tau二聚体，并在热休克蛋白（HSP），行为，突触和FYN中转化依赖性缺陷，这是ABETA毒性中浸渍的Tau激酶。与姜黄素相反，我们的数据表明，另一种多酚菲塞肽可以减少总TAU和PS422单体。 We propose to study the impact of fishetin, a CDK5 inhibitor and SIRT1 activator (fisetin) found in fruits (strawberries) an its synergism with curcumin on pTau species and synaptic and cognitive deficiencies in a tauopathy model, comparing effectiveness 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, infection, synaptic proteins, fyn, cdk5, microtubule/ transport and mitochondria defects, behavior, tau oligomers and tau species. 目标：目标1，以确定在有或没有ICV输注a的Hutautg小鼠中Fisetin与特定的TAU聚集抑制剂的相对效率。目标2：确定hutau TG小鼠中渔蛋白和姜黄素之间的协同作用（有或不含ICV输注A？）。 假设：干预措施用于澄清候选者（Tau物种，CDK5或FYN激活，增强HSP的反应或自噬）的目标参与度和重要性，包括识别某些可能有益的TAU物种。 1。Fisetin将减少CDK5的TAU转化相关的过度激活，而不是FYN。 2。菲塞丁可减少单体和不溶性PTAU，并增加未磷酸化的tau并稳定微管；但是，这不会导致低聚物的减少，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，鱼素不会纠正依赖转化的热冲击反应。 4。姜黄素，但不是渔丁素会减少总FYN，TAU低聚物，CP13 PTAU的重新分布，以及cp13 ptau，以及综合和认知缺陷，而不是nft和不溶性的tau。 5。姜黄素但不是渔民将刺激Akt和下游，P214 TAU或MARK/ P262 TAU。 6。菲塞丁通过SIRT1激活激活大自自大的途径，而姜黄素会增加伴侣介导的微噬细胞。 7。可生物利用的fisetin和姜黄素将减少PTAU的不同致病物种，但协同起作用可减少认知缺陷，NFT，TAU低聚物和不溶性tau，并纠正NR2B或PSD-95受体复合物复合物在老年HTAU小鼠中的受体复杂失调。 8。抗聚集tau抑制剂，但不能减少包括低聚物的PTAU，但不降低预先形成的不溶性沉积物或A诱导的缺陷以及正确的突触和认知能力，但不是HSPS缺陷。 9。具有Tau特异性骨料抑制的A +TAU模型将有助于描述A vs.tau机制和干预措施的相对效率。 潜在的结果：因为渔蛋白直接抑制CDK5，稳定微管并刺激自噬途径，但对FYN没有影响，而姜黄素会降低致病性Fyn并选择性地减少Tau寡聚物，因此渔夫应与Tau糖（Tau）寡聚蛋白有所不同，因此Tau dau激酶/磷酸化酶平衡，PTAU和PROCHATES。有些但不是所有PTAU物种都将与NR2B/ PSD-95受体复合物失调以及影响认知，突触和炎症终点相关。总而言之，这些研究既是机械的又是转化，在鉴定可溶性有毒tau物种和排除无毒物种方面的知识以及受保护的tau间隙途径。目标的完成将在展示tau聚集，突触/神经保护，感染，自噬和HSP之间的相互关系方面向前发展。