Human tau neurodegeneration in Alzheimer's

描述(由申请人提供)： 神经退行性变可能是由Huntingtin和其他CAG-Repeat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形成的。在转基因模式下，额叶颞叶痴呆(FTD)中的tau突变(如p301L)会导致tau聚集和神经元死亡。在阿尔茨海默病(AD)中，AB直接毒性、tau和突触核蛋白病理与神经退行性变之间的相对作用和相互关系尚不清楚。然而，最近来自转基因的数据表明，导致AD的β淀粉样蛋白(AB)可能导致CNS tau/tangle病理。我们的初步数据表明，与输注赋形剂(HLD)相比，将低剂量的可溶性AB寡聚体注入转P301L基因的人tau转基因细胞中，会导致tau病变、洗涤剂不溶性磷酸和神经元丢失。与人类WT小鼠或TG阴性小鼠相比，P301L突变与AB诱导的认知障碍的易感性有关，这是一项新的发现。这可能涉及氧化损伤和半胱氨酸氨基转移酶和tau激酶的激活。针对细胞内蛋白聚集体毒性的主要防御措施是诱导热休克蛋白(HSPs)作为细胞应激反应的一部分。在CAG重复、突触核蛋白聚集和缺血模型中，HSP70转基因过表达可防止神经变性，可能是因为这一途径是消除有毒蛋白质聚集所必需的。在这项提案中，我们将研究可溶性Abeta42输注对人类WT、p301L和V337基因组转基因小鼠tau病理、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假定保护剂。我们假设tau病理终点将被caspase激活抑制剂(Aim 3)和主要的tau激酶GSK3B(Aim 4)部分改善，但通过NSAID/抗氧化剂(Aim 5)的治疗完全改善，NSAID/抗氧化剂被证明是CNS细胞应激反应的有效增强剂，特别是HSP70。我们的建议将证明AB42寡聚体和tau依赖的神经元内ptau聚集物和神经退行性变导致严重的认知缺陷(更好的AD模型)。此外，我们预计姜黄素，一种非甾体抗炎药/抗氧化剂，增强HSP70的诱导，将被证明比GSK3B，COX-2抑制剂，阻断PERK或维生素E，在这个模型中更有效地保护tau病变和神经变性。成功的结果可能会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.