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

基本信息

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
项目类别：
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&apos 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

项目摘要

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2亿个人有慢性创伤性脑病（CTE）的风险。 CTE与接触重复性头部撞击（RHI）的暴露密切相关，例如通过联系运动和军事活动。神经病理学上，CTE是由逐步积累的高磷酸化的tau（p-tau），由小胶质细胞神经炎症增强。 RHI暴露会诱发小胶质细胞炎症甚至在tau病理发作之前，但是连接RHI的机制， CTE中的炎症和Tau是未知的，代表了主要的知识差距。适当的溶酶体功能小胶质细胞是P-TAU清除的关键机制，如果受损，则会导致P-TAU沉积。最近，发现CTE中更严重的TAU病理TMEM106B的遗传危险因素会影响小胶质细胞炎症，tau病理和CTE严重程度。 TMEM106B是溶酶体相关的蛋白质，风险等位基因产生较大，酸化较差的溶酶体，指出CTE中溶酶体加工的潜在作用发病。此外，也来自CTE组织的初步单核RNA测序（SNRNASEQ）数据提出对小胶质细胞中溶酶体功能的改变。这些数据导致我们假设暴露于RHI 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，空间转录组学，和多重免疫荧光，以嘲笑rhi诱导的小胶质细胞的遗传基础功能障碍并理解其作为赋予TMEM106B遗传风险的潜在机制的作用 CTE中的P-TAU病理学。在AIM 1中，我们将评估小胶质细胞的细胞和空间分辨的基因组变化具有CTE的个体的成绩单。这将揭示以下溶酶体功能障碍的基因组基础 RHI并允许我们将这些更改定位到P-TAU沉积区域。在AIM 2中，我们将检查小胶质细胞溶酶体结构和含量，溶酶体功能的标记，应力和蛋白酶表达。然后我们会分析这些变化与TMEM106B等位基因状况，RHI暴露年份以及存在以及存在以及 CTE病理的严重程度。 McKee和Cherry Labs（赞助商和共同发起人）的先前工作初步数据已验证了所提出的技术。这项工作将是第一个研究小胶质溶酶体的工作功能障碍是CTE病理和遗传风险的机制，将大大推动或理解早期疾病过程以及新型生物标志物和治疗靶向的未来发现机制。