Microglial Lysosomal Dysfunction Following Head Trauma Contributes to Tau Pathology in Chronic Traumatic Encephalopathy

头部创伤后小胶质细胞溶酶体功能障碍导致慢性创伤性脑病的 Tau 病理学

• 批准号: 10677185
• 负责人: Morgane LMD Butler
• 金额: $ 4.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-03-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677185
• 关键词: Address; Age; Alleles; Alzheimer' s Disease; Autopsy; Bioinformatics; Blood Vessels; Brain; CTSB gene; Cathepsins B; Cd68; Computer Analysis; Craniocerebral Trauma; Data; Deposition; Development; Diagnosis; Diagnostic; Disease; Disease Pathway; Exposure to; Frontotemporal Dementia; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Carriers; Genetic Risk; Genetic Transcription; Genomics; Goals; Human; Imaging Techniques; Immunofluorescence Immunologic; Impairment; Individual; Inflammation; Knowledge; Label; Lesion; Link; Lipofuscin; Lysosomes; Measures; Mediating; Microglia; Microscopy; Military Personnel; Mission; Morbidity - disease rate; Nerve Degeneration; Neurodegenerative Disorders; PECAM1 gene; Pathogenesis; Pathology; Peptide Hydrolases; Phagocytosis; Populations at Risk; Positioning Attribute; Predisposition; Process; Proteins; Public Health; Research; Risk; Role; Severities; Shapes; Single Nucleotide Polymorphism; Statistical Models; Stress; Structure; Tauopathies; Techniques; Therapeutic; Therapeutically Targetable; Tissues; Training; Transcript; United States National Institutes of Health; Work; brain tissue; chronic traumatic encephalopathy; contact sports; diagnostic biomarker; frontal lobe; genetic risk factor; genetic signature; head impact; hyperphosphorylated tau; lysosomal proteins; military service; mortality; neuroinflammation; neuropathology; novel; novel diagnostics; novel marker; novel therapeutic intervention; novel therapeutics; pre-doctoral; quantitative imaging; repository; risk variant; single nucleus RNA-sequencing; tau Proteins; tau-1; transcriptomics

Abstract: More than 200 million individuals are at risk for chronic traumatic encephalopathy (CTE) each year. CTE is strongly associated with exposure to repetitive head impacts (RHI) such as those received through contact sports and military activities. Neuropathologically, CTE is defined by progressive accumulation of hyperphosphorylated tau (p-tau) which is potentiated by microglial neuroinflammation. RHI exposure can induce microglial inflammation even before the onset of tau pathology, but the mechanisms connecting RHI, inflammation, and tau in CTE are unknown, representing a major knowledge gap. Proper lysosomal function in microglia is a key mechanism of p-tau clearance that, when impaired, contributes to p-tau deposition. Recently, a genetic risk factor for more severe tau pathology in CTE, TMEM106b, was found to influence microglial inflammation, tau pathology, and CTE severity. TMEM106b is a lysosome-associated protein and the risk allele produces larger, poorly acidifying lysosomes, pointing to a potential role for lysosomal processing in CTE pathogenesis. Furthermore, preliminary single nucleus RNA sequencing (snRNAseq) data from CTE tissue also suggest an alteration to lysosomal functions in microglia. These data led us to hypothesize that exposure to RHI triggers persistent microglial lysosomal dysfunction which is exacerbated by TMEM106b genetic risk allele and drives p-tau deposition in CTE. To address this hypothesis, we will utilize snRNAseq, spatial transcriptomics, and multiplex immunofluorescence to tease apart the genetic underpinnings of RHI-induced microglial lysosomal dysfunction and understand its role as a potential mechanism conferring TMEM106b genetic risk for more severe p-tau pathology in CTE. In Aim 1 we will assess cellularly and spatially resolved genomic changes to microglial transcripts in individuals with CTE. This will reveal the genomic underpinnings of lysosomal dysfunction following RHI and allow us to localize these changes to regions of p-tau deposition. In Aim 2 we will examine microglial lysosomal structure and content, markers of lysosomal function, stress, and protease expression. We will then analyze the relationship of these changes to TMEM106b allele status, years of RHI exposure, and presence and severity of CTE pathology. Previous work in the McKee and Cherry Labs (Sponsor and co-sponsor) and preliminary data have validated the proposed techniques. This work will be the first to study microglial lysosomal dysfunction as a mechanism of CTE pathology and genetic risk which will significantly advance or understanding of an early disease process and direct future discovery of novel biomarkers and therapeutically targetable mechanisms.

摘要：每年有超过2亿人面临慢性创伤性脑病(CTE)的风险。 CTE与暴露于重复性头部撞击(RHI)密切相关，例如通过 联系体育和军事活动。在神经病理学上，CTE的定义是进行性积聚 过度磷酸化的tau(p-tau)，因小胶质细胞神经炎而加重。接触RHI可导致 小胶质细胞炎症甚至在tau病理之前就开始了，但连接RHI、 CTE中的炎症和tau尚不清楚，这是一个重大的知识缺口。正常的溶酶体功能 小胶质细胞是p-tau清除的关键机制，当受损时，有助于p-tau沉积。最近， CTE中更严重的tau病理的遗传危险因素TMEM106b被发现影响小胶质细胞 炎症、tau病理和CTE严重程度。TMEM106b是一种溶酶体相关蛋白和易感等位基因 产生较大的、酸化较差的溶酶体，表明溶酶体处理在CTE中具有潜在的作用 发病机制。此外，来自CTE组织的初步单核RNA测序(SnRNAseq)数据也 提示小胶质细胞的溶酶体功能发生了变化。这些数据让我们假设暴露在RHI中 触发持续性小胶质细胞溶酶体功能障碍，TMEM106b遗传风险等位基因和 在CTE中驱动p-tau沉积。为了解决这一假设，我们将利用SnRNAseq，空间转录， 和多重免疫荧光以梳理RHI诱导的小胶质细胞溶酶体的遗传基础 功能障碍并理解其作为TMEM106b遗传风险更严重潜在机制的作用 CTE中的P-tau病理改变。在目标1中，我们将评估小胶质细胞的细胞和空间分辨基因组变化。 CTE患者的成绩单。这将揭示溶酶体功能障碍的基因组基础 RHI，并允许我们将这些变化定位于p-tau沉积区域。在目标2中，我们将检查小胶质细胞 溶酶体的结构和含量、溶酶体功能的标志物、应激和蛋白酶的表达。到时候我们会的 分析这些变化与TMEM106b等位基因状态、RHI暴露年限以及存在和 CTE病理严重程度。麦基和樱桃实验室以前的工作(赞助商和共同赞助商)和 初步数据验证了所提出的技术。这项工作将是首次研究小胶质细胞溶酶体。 功能障碍是CTE病理和遗传风险的一个机制，这将显著促进或理解 早期疾病进程和未来直接发现新的生物标记物和治疗靶点 机制。