Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease

补编--摘要 Tau与阿尔茨海默病(AD)和许多其他脑部疾病有关。然而，目前还不确定tau如何 导致神经元功能障碍和变性，部分原因是实验模型没有优化到 在与疾病相关的情况下，比较不同tau物种的相对致病性。MAPT的突变，即 编码tau的基因，导致额颞叶变性(FTLD)而不是AD。相比之下，稀有的A152T Tau基因的变异会增加患这两种疾病的风险。这些联系值得进一步探讨，尤其是 作为表达FTLD-突变体tau的模型，tau被广泛用于研究tau在AD中的作用和开发新的AD治疗方法。 临床阿尔茨海默病发病前，脑内淀粉样蛋白b(Ab)多肽异常积聚，许多AD 患者至少有一个载脂蛋白(Apo)E4等位基因，这是AD最重要的遗传风险因素。因此， 项目3将产生将人类抗体和apoE4表达与近生理学相结合的新小鼠模型 与大多数AD患者一样，人类tau的水平是野生型的，或者携带A152T替换，这会增加 广告风险。对新模型进行全面的功能、病理和转录分析，有待进行 与项目1、2和4以及核心B合作，应该会对以下项目的差异影响产生新的见解 这些tau物种及其在痴呆发病机制中的作用。项目3还将调查Tau是否 增加AD风险或导致FTLD的物种在对神经元和 神经网络。直到我们知道哪些形式的tau在不同的条件下最具致病性，最 在我们看来，治疗tau的务实方法是部分降低总体tau水平，这是很好的耐受性。 而且在更传统的模式中也有好处。因此，我们将使用tau靶向反义寡核苷酸来 在共表达人抗体和载脂蛋白E4的模型中降低人tau水平。单核/单细胞 转录分析将用于识别特定细胞类型的基因表达变化以及新的 可能介导tau致病效应或tau有益效应的分子和细胞机制 还原。这些分析将帮助项目1和2区分apoE4和apoE4的致病机制 依赖于或不依赖于tau的AB。他们还可以识别新的分子和细胞机制， 介导tau序列特异性效应。所要求的补充将允许博士后学者从 在与健康相关的科学中未被充分代表的背景，以促进在 项目3，同时从以AD为重点的更大范围内的培训中受益 跨学科项目。

SUPPLEMENT – 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, Project 3 will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is wildtype, as in most AD patients, or carries the A152T substitution, which increases AD risk. Comprehensive functional, pathological, and transcriptomic analyses of the new models, to be carried out 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. Project 3 will also investigate whether tau species that increase AD risk or cause FTLD differ in their effects on the integrity and functions of neurons and neural networks. 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 more conventional models. We will therefore use tau-targeting antisense oligonucleotides to reduce human tau levels in models co-expressing human Ab and apoE4. Single-nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes as well as novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau. They could also identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects. The requested supplement will allow a postdoctoral scholar from a background that is underrepresented in the health-related sciences to contribute to the experiments proposed in Project 3 and, at the same time, to benefit from training within the larger context of this AD-focused interdisciplinary program.