Mechanisms and Consequences of Tau Internalization and Aggregation in the Central Nervous System

tau蛋白的聚集发生在一系列神经退行性疾病中，包括阿尔茨海默病1。tau聚集体的存在，也称为神经元缠结（NFT），与患者的疾病症状和临床严重程度相关2。除了tau病理学之外，脑中的先天免疫细胞（特别是小胶质细胞和星形胶质细胞）介导神经炎症的能力也被认为是阿尔茨海默病发病机制的重要贡献者。不幸的是，关于tau聚集如何在中枢神经系统（CNS）中刺激以及如何影响神经免疫通路的详细了解仍然不清楚。在完成的K99阶段，我们发现了tau摄取的细胞受体LRP 1，并开发了单细胞RNA测序方法的专业知识。在R 00阶段，我们将扩展在K99指导阶段获得的知识，并将研究重点放在与小胶质细胞tau调节和细胞对tau物理状态的影响相关的问题上。在本提案的前半部分，我们将研究定义tau的小胶质细胞识别的分子途径，并破译哪些基因对这一过程最关键。在下半年，我们将利用我们的功能基因组学专业知识来了解tau从头聚集的关键途径。本文概述的新的实验方法和全面的分析将发展我们对致病性tau调节的理解。此外，有了这种机制的见解，我们将能够设想新的治疗策略，如阿尔茨海默氏病。 Mandelkow，E. M. & Mandelkow，E.神经退行性变中tau蛋白的生物化学和细胞生物学研究。Cold Spring Harb Perspect Med 2，a006247，doi：10.1101/cshperspect.a006247（2012）。 Haroutunian，V.，Davies，P.，Vianna，C.，巴克斯鲍姆，J. D. & Purohit，D. P. Tau蛋白异常与阿尔茨海默病型痴呆的进展相关。Neurobiol Aging 28，1-7，doi：10.1016/j.neurobiolaging.2005.11.001（2007）。

The aggregation of the protein tau occurs in a range of neurodegenerative diseases, including Alzheimer’s Disease1. The presence of tau aggregates, also known as neurofibrillary tangles (NFTs), is correlated with disease symptoms and clinical severity in patients2. In addition to tau pathology, the ability of innate immune cells in the brain, particularly microglia and astrocytes, to mediate neuroinflammation has been implicated as a significant contributor to Alzheimer’s Disease pathogenesis. Unfortunately, a detailed understanding of how tau aggregation is spurred in the central nervous system (CNS) and how this influences neuroimmune pathways has remained unclear. In the completed K99 phase, we discovered a cellular receptor for tau uptake, LRP1, and developed expertise in single-cell RNA sequencing methods. In the R00 phase, we will expand on the knowledge gained in the K99 mentored phase and focus the research on questions related to microglial tau regulation and cellular influences on tau’s physical state. In the first half of this proposal we will examine the molecular pathways that define microglial recognition of tau and decipher which genes are most critical for this process. In the second half we will leverage our functional genomics expertise to understand pathways critical for de novo aggregation of tau. The novel experimental methods and comprehensive analyses outlined herein will develop our understanding of pathogenic tau regulation. Further, with this mechanistic insight we will be able to envision novel therapeutic strategies for diseases such as Alzheimer’s Disease. Mandelkow, E. M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2, a006247, doi:10.1101/cshperspect.a006247 (2012). Haroutunian, V., Davies, P., Vianna, C., Buxbaum, J. D. & Purohit, D. P. Tau protein abnormalities associated with the progression of alzheimer disease type dementia. Neurobiol Aging 28, 1-7, doi:10.1016/j.neurobiolaging.2005.11.001 (2007).