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 与重复性头部撞击 (RHI) 密切相关，例如通过 接触性运动和军事活动。在神经病理学上，CTE 的定义是逐渐积累 过度磷酸化的 tau (p-tau) 会因小胶质细胞神经炎症而增强。 RHI 暴露可诱发 小胶质细胞炎症甚至在 tau 病理学发生之前就已存在，但连接 RHI 的机制， 炎症和 CTE 中的 tau 蛋白尚不清楚，这是一个重大的知识差距。适当的溶酶体功能 小胶质细胞是 p-tau 清除的关键机制，当其受损时，会导致 p-tau 沉积。最近， TMEM106b 是 CTE 中更严重 tau 病理学的遗传风险因素，被发现会影响小胶质细胞 炎症、tau 病理学和 CTE 严重程度。 TMEM106b 是一种溶酶体相关蛋白和风险等位基因 产生较大、酸化较差的溶酶体，表明溶酶体加工在 CTE 中具有潜在作用 发病。此外，来自 CTE 组织的初步单核 RNA 测序 (snRNAseq) 数据也 表明小胶质细胞溶酶体功能发生改变。这些数据使我们推测暴露于 RHI 引发持续性小胶质细胞溶酶体功能障碍，TMEM106b 遗传风险等位基因会加剧这种功能障碍， 驱动 CTE 中的 p-tau 沉积。为了解决这个假设，我们将利用 snRNAseq、空间转录组学、 和多重免疫荧光来梳理 RHI 诱导的小胶质细胞溶酶体的遗传基础 功能障碍并了解其作为赋予 TMEM106b 遗传风险的潜在机制的作用，导致更严重的疾病 CTE 中的 p-tau 病理学。在目标 1 中，我们将评估小胶质细胞的细胞和空间解析基因组变化 患有 CTE 的个体的转录本。这将揭示溶酶体功能障碍的基因组基础 RHI 使我们能够将这些变化定位到 p-tau 沉积区域。在目标 2 中，我们将检查小胶质细胞 溶酶体结构和含量、溶酶体功能标记、应激和蛋白酶表达。我们随后将 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 病理的严重程度。之前在 McKee 和 Cherry 实验室（赞助商和共同赞助商）的工作以及 初步数据验证了所提出的技术。这项工作将是第一个研究小胶质细胞溶酶体的工作 功能障碍作为 CTE 病理学和遗传风险的机制，将显着推进或理解 早期疾病过程和未来直接发现新型生物标志物和治疗靶向 机制。