Human tau neurodegeneration in Alzheimer's

描述（由申请人提供）： 神经变性可以通过由亨廷顿蛋白和其他CAG重复疾病蛋白、α-突触核蛋白和tau蛋白形成的不溶性神经元内蛋白聚集体的积累来产生。 额颞叶痴呆（FTD）中的Tau突变（如p301 L）导致转基因模式中的Tau聚集和神经元死亡。 在阿尔茨海默病（AD）中，直接AB毒性、tau和突触核蛋白病理学以及神经变性之间的相对作用和相互关系仍不清楚。 然而，最近来自转基因的数据显示，导致AD的β淀粉样蛋白（AB）可能诱导CNS tau/缠结病理。 我们的初步数据表明，与输注载体（HLD）相比，输注到具有P301 L转基因的人tau转基因中的低剂量可溶性AB寡聚物诱导tau病理学、去污剂不溶性磷酸化tau和神经元损失。 与人WT小鼠或Tg阴性小鼠相比，P301 L突变与AB诱导的认知丧失的脆弱性相关，这是一项新发现。 这可能涉及氧化损伤和半胱天冬酶和tau激酶激活。 一个主要的识别防御细胞内蛋白质聚集体的毒性是诱导热休克蛋白（HSP）的细胞应激反应的一部分。 HSP 70转基因过表达在CAG重复序列、突触核蛋白聚集体和缺血模型中保护神经变性，推测是因为需要该途径来消除有毒的蛋白质聚集体。 在本提案中，我们将研究可溶性A β 42输注对人WT、p301 L和V337基因组转基因小鼠中tau病理学、神经变性（Aim 1）和认知缺陷（Aim 2）的影响，并测试两种具有不同机制的推定保护剂。 我们假设tau病理学终点将通过半胱天冬酶活化抑制剂（Aim 3）和主要tau激酶GSK 3B（Aim 4）部分改善，但通过NSAID/抗氧化剂（Aim 5）治疗完全改善，NSAID/抗氧化剂显示为CNS细胞应激反应的有效增强剂，特别是HSP 70。 我们的提案将证明AB 42寡聚体和tau依赖性神经元内ptau聚集包涵体和神经变性导致严重的认知缺陷（更好的AD模型）。 此外，我们预期姜黄素（一种增强HSP 70诱导的NSAID/抗氧化剂）将证明比阻断pERK或维生素E的GSK 3 B、考克斯-2抑制剂更有效地保护该模型中的tau病理和神经变性。 成功的结果可能对阿尔茨海默氏症和其他与包容相关的神经退行性疾病的治疗产生深远的影响。

DESCRIPTION (provided by applicant): Neurodegeneration can be produced by the accumulation of insoluble intraneuronal protein aggregates formed from Huntingtin and other CAG-repeat disease proteins, a-synuclein and tau protein. Tau mutations in frontal temporal dementias (FTD) such as p301L lead to tau aggregation and neuron death in transgenic modes. In Alzheimer's (AD), the relative roles and interrelationships between direct AB toxicity, tau and synuclein pathology, and neurodegeneration remain unclear. However, recent data from transgenics show that beta amyloid (AB) which causes AD, may induce CNS tau/tangle pathology. Our preliminary date indicate that compared to infusion of vehicle (HLD), low dose soluble AB oligomers infused into human tau transgenics with P301L transgene induces tau pathology, detergent insoluble phosphotau and neuron loss. The P301L mutation is associated with vulnerability to AB induced cognitive loss compared to human WT mice or Tg negative mice, a novel finding. This may involve oxidative damage and caspase and tau kinase activation. A major identified defense against toxicity from intracellular protein aggregates is the induction of heat shock proteins (HSPs) as part of the cellular stress response. HSP70 transgene overexpression protects against neurodegeneration in CAG repeat, synuclein aggregate and ischemia models, presumable because this pathway is needed to eliminate toxic aggregates of proteins. In this proposal we will examine the impact of soluble ABeta42 infusion on tau pathology, neurodegeneration (Aim 1) and cognitive deficits (Aim 2) in human WT, p301L and V337 genomic transgenic mice and test two putative protective agents with distinct mechanisms. We hypothesize that tau pathology endpoints will be partially ameliorated by inhibitors of caspase activation (Aim 3) and a major tau kinase, GSK3B (Aim 4)-but completely ameliorated by treatment with an NSAID/antioxidant (Aim 5) shown to be an effective potentiator of the CNS cellular stress response, notably HSP70. Our proposal will demonstrate AB42 oligomer-and tau-dependent intraneuronal ptau aggregate inclusions and neurodegeneration leading to severe cognitive deficits (a better AD model). Further, we anticipate that curcumin, an NSAID/antioxidant that potentiates HSP70 induction will prove more effective than GSK3B, Cox-2 inhibitors that block pERK or vitamin E in protecting against tau pathology and neurodegeneration in this model. Successful results may have profound implications for treatment of Alzheimer's and other inclusion-related neurodegenerative diseases.