Project 3: Roles of Tau Levels, Sequence and Interactors in Neural Network Dysfunction of Alzheimer's Disease

项目 3：Tau 水平、序列和相互作用因子在阿尔茨海默病神经网络功能障碍中的作用

• 批准号: 10271128
• 负责人: Lennart Mucke
• 金额: $ 88.8万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271128
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amino Acid Substitution; Amyloid beta-Protein; Amyloid deposition; Antisense Oligonucleotides; Apolipoprotein E; Behavioral; Brain; Brain Diseases; Cell Nucleus; Cells; Clinical; Cognitive deficits; Collaborations; Dementia; Disease; Etiology; Experimental Models; Frontotemporal Lobar Degenerations; Gene Expression; Human; Impaired cognition; Intervention; Knock-in; MAPT gene; Mediating; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Phenotype; Physiological; Protein Isoforms; Risk; Role; Senile Plaques; Synapses; Therapeutic; Ursidae Family; Variant; Wild Type Mouse; abeta accumulation; apolipoprotein E-4; cell type; early onset; experimental study; familial Alzheimer disease; gene product; genetic risk factor; insight; mouse model; mutant; network dysfunction; neural network; novel; overexpression; pathogen; prevent; relating to nervous system; tau Proteins; tau mutation; tau-1; transcriptomics

PROJECT 3 – SUMMARY Tau contributes to Alzheimer’s disease (AD) and many other brain diseases. However, it is uncertain how tau causes neuronal dysfunction and degeneration, in part because experimental models are not optimized to compare the relative pathogenicity of different tau species in disease-relevant contexts. Mutations in MAPT, the gene encoding tau, cause frontotemporal lobar degeneration (FTLD) instead of AD. In contrast, the rare A152T variant of tau increases risk for both types of diseases. These associations merit further exploration, especially as models expressing FTLD-mutant tau are widely used to study tau in AD and to develop novel AD treatments. Clinical AD onset is preceded by abnormal accumulations of amyloid-b (Ab) peptides in brain, and many AD patients have at least one apolipoprotein (apo) E4 allele, the most important genetic risk factor for AD. Therefore, we will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is (1) wildtype, as in most AD patients, (2) carries the A152T substitution, which increases AD risk, or (3) bears the P301S mutation, which causes FTLD and is widely used in overexpression models. Comprehensive functional, pathological, and transcriptomic analyses of the new models, in collaboration with Projects 1, 2, and 4 and Core B, should yield new insights into differential effects of these tau species and their roles in the pathogenesis of dementia. We hypothesize that tau species that increase AD risk or cause FTLD differ in their effects on the integrity and function of neurons and neural networks, especially when combined with Aβ and apoE4. Until we know which forms of tau are most pathogenic in different conditions, the most pragmatic therapeutic approach to tau in our view is partial reduction of overall tau levels, which is well tolerated and has benefits in conventional models. We will therefore use tau-targeting antisense oligonucleotides (ASOs) to (1) determine whether reducing human tau can diminish neural network dysfunction, neurodegeneration and cognitive decline in models co-expressing human Ab and apoE4, (2) define the optimal timing for this intervention, and (3) reveal the most critical co-pathogenic mechanisms of tau. We hypothesize that ASO- mediated tau reduction will diminish not only tau pathology in one or more of the new models, but also synaptic deficits, neural network dysfunction, and cognitive deficits, even though it is unlikely to reduce amyloid deposition or plaque-associated microgliosis. This experiment should help determine when tau reduction must be initiated relative to the onset of cognitive deficits for it to have therapeutic benefits in AD-relevant contexts. Single- nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes and novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will also help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau and could identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects in the absence or presence of AD-relevant co-pathogens.

项目3 - 摘要 Tau为阿尔茨海默氏病（AD）和许多其他脑部疾病做出了贡献。但是，不确定如何 引起神经元功能障碍和变性，部分原因是实验模型未优化 比较与疾病相关的环境中不同TAU物种的相对致病性。 Mapt中的突变， 编码tau的基因，导致额颞叶变性（FTLD）而不是AD。相反，罕见的A152T Tau的变体增加了两种疾病的风险。这些协会值得进一步探索，特别是 由于表达FTLD突变tau的模型被广泛用于研究AD中的TAU并开发新的AD处理。 临床AD发作之前是大脑中淀粉样蛋白B（AB）肽的异常积累，许多AD 患者至少有一个载脂蛋白（APO）E4等位基因，这是AD最重要的遗传危险因素。所以， 我们将生成新的鼠标模型，将人类AB和APOE4表达与接近生理水平相结合 （1）WildType的人类Tau（与大多数AD患者一样，（2）携带A152T替代，这增加了AD 风险或（3）带有P301S突变，该突变导致FTLD并广泛用于过表达模型。 与新模型的全面功能，病理和转录分析与 项目1、2和4和核心B应该对这些Tau物种及其差异影响产生新的见解 在痴呆发病机理中的作用。我们假设会增加AD风险或引起FTLD的Tau物种 它们对神经元和神经元的完整性和功能的影响有所不同，尤其是当合并时 与Aβ和APOE4。直到我们知道哪种形式的tau在不同条件下最致病的是 在我们看来，对tau的务实理论方法是部分降低了tau级别，这是宽容的 并在常规模型中有好处。因此，我们将使用靶向tau的反义寡核苷酸（ASO） （1）确定减少人tau是否可以减少神经元网络功能障碍，神经退行性和 共同表达人AB和APOE4的模型的认知能力下降，（2）定义了最佳时机 干预，（3）揭示了tau的最关键的共同致病机制。我们假设这是 介导的tau降低不仅会减少一个或多个新模型中的tau病理学，还会减少突触 缺陷，神经网络功能障碍和认知缺陷，尽管不太可能减少淀粉样蛋白沉积 或斑块相关的小胶质细胞增多症。该实验应有助于确定何时必须启动tau 相对于认知缺陷的发作，它在与广告相关的情况下具有治疗益处。单身的- 细胞核/单细胞转录组分析将用于鉴定细胞型特异性基因表达变化 以及可能介导tau的致病作用或有益作用的新型分子和细胞机制 tau还原。这些分析还将帮助项目1和2在致病机制之间不同 apoE4和AB的做法或不依赖于tau，可以鉴定出新的分子和细胞机制， 在不存在或存在与AD相关的共染色的情况下介导Tau序列特异性效应。