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

Tau蛋白的聚集出现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，也被称为神经原纤维缠结(NFTs)，与患者的疾病症状和临床严重程度相关。除了tau病理，大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被认为是阿尔茨海默病发病的重要因素。不幸的是，关于tau聚集是如何在中枢神经系统(CNS)中被刺激以及它如何影响神经免疫通路的详细了解还不清楚。在完成的K99阶段，我们发现了摄取tau的细胞受体LRP1，并发展了单细胞RNA测序方法的专业知识。在R00阶段，我们将扩展在K99指导阶段获得的知识，重点研究与小胶质细胞tau调节相关的问题以及细胞对tau物理状态的影响。在这项提案的前半部分，我们将研究定义小胶质细胞识别tau的分子通路，并破译哪些基因对这一过程最关键。在下半部分，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加深我们对致病tau调控的理解。此外，有了这种机械性的洞察力，我们将能够设想阿尔茨海默病等疾病的新治疗策略。 神经纤维变性中tau蛋白的生物化学和细胞生物学。《冷泉港透视医学2》，a006247，DOI：10.1101/cshperspect.a006247(2012年)。 Haroutunian，V.，Davies，P.，Vianna，C.，Buxbaum，J.D.&PuroHit，D.P.Tau蛋白异常与阿尔茨海默病类型痴呆的进展有关。Neurobiol Aging 28，1-7，DOI：10.1016/J.Neurobioling.2005.11.001(2007年)。

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).