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。