Influence of APOE4 genotype on microglial pathobiology and tau pathology after repetitive mTBI

APOE4 基因型对重复 mTBI 后小胶质细胞病理学和 tau 病理学的影响

• 批准号: 10575479
• 负责人: Joseph O Ojo
• 金额: $ 16.34万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575479
• 关键词: AD transgenic mice; Ablation; Address; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Animal Model; Animals; Apolipoprotein E; Attenuated; Automobile Driving; Autopsy; Biochemical; Biochemical Markers; Bioinformatics; Biology; Brain; Brain Injuries; Calendar; Cells; Cellular Neurobiology; Chronic; Clinical; Clinical Trials; Communication; Contracts; Cre-LoxP; Data; Data Analyses; Data Set; Dedications; Deposition; Development; Disease associated microglia; Doctor of Philosophy; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; Event; Exposure to; Failure; Flow Cytometry; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Goals; Health; Heterogeneity; Histopathology; Human; Individual; Inflammatory; Inflammatory Response; Injury; Interdisciplinary Study; Investigation; Lesion; Longitudinal Studies; Macrophage; Mediating; Microglia; Modeling; Molecular; Molecular Analysis; Molecular Neurobiology; Mus; Nerve Degeneration; Neuroglia; Neuroimmune; Neurologic; Neurologic Dysfunctions; Neurons; Operative Surgical Procedures; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phenotype; Play; Population; Postdoctoral Fellow; Principal Investigator; Procedures; Process; Protein Biochemistry; Protein Isoforms; Rationalization; Reporting; Research; Research Design; Research Personnel; Risk; Risk Factors; Role; Sampling; Severities; Supervision; Synapses; TBI treatment; Tamoxifen; Tauopathies; Techniques; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Traumatic Brain Injury; Treatment Protocols; Up-Regulation; Western Blotting; Work; apolipoprotein E-4; axon injury; behavioral outcome; brain tissue; comorbidity; cost; density; disability; effective therapy; experience; experimental study; exposed human population; functional genomics; genetic manipulation; genetic risk factor; genetic signature; human model; human study; hyperphosphorylated tau; immune cell infiltrate; injured; longitudinal analysis; longitudinal design; member; mild traumatic brain injury; mouse model; neurodegenerative phenotype; neuroinflammation; neuropathology; new therapeutic target; novel; patient population; pharmacologic; preclinical study; programs; prospective; protein expression; repaired; response; tau Proteins; tau-1; tissue repair; transcriptome sequencing; transcriptomics; transgenic model of alzheimer disease

One of the hallmark, chronic, features of repetitive mild TBI (r-mTBI) is the deposition of phosphorylated tau in neurons. Tau lesions are also one of the main hallmark features of ADRD. It remains unknown what specific molecular triggers precipitate the path towards this distinct TBI related neurodegenerative phenotype. The E4 allele is a major genetic risk factor for AD; individuals carrying 1 copy have a 2-3 fold risk for AD, while those with 2 copies have a 15-fold risk compared to E3 carriers. Despite some contradictory studies, the E4 allele has long been associated with a poor outcome after TBI, but the role played by APOE in response to TBI is still unknown and well-designed longitudinal studies are needed. Conducting such studies in humans remains challenging as epidemiological and prospective data are lacking, plus the heterogeneity of TBI etiology, including (but not limited to) severity level, age, comorbidities and time post-TBI, present an enormously confounding problem. Thus, the best way to address this question is in translationally relevant, well characterized and controlled animal models, wherein key predisposing genetic factors can be targeted and expressed, and findings from longitudinal analyses can be related to the limited autopsy information from human TBI cases who have died at different timepoints after their injury. We have developed and characterized such mouse models of r-mTBI, which recapitulate many features of human TBI pathology. In recent work, we have exposed human APOE-targeted replacement mice (APOE-TR), mice humanized for Tau (TauKI) and crosses of these mice (E-Tau) to our r-mTBI paradigm, and observe TBI-dependent pTau pathology. From these studies we have also revealed that the E4 allele augments the proinflammatory microglial response and Tau pathology in injured mice compared to E3. APOE is upregulated in disease associated microglia, which has been reported in AD brains. In our r-mTBI model we have also confirmed an increase in microglial specific APOE gene expression. Disease associated microglia have been reported to drive the outcome and pace of APOE4-dependent neurodegeneration in AD transgenic models; yet very little is known about their contribution in driving APOE4 mediated effects after r-mTBI. We will address these unknowns using mouse models expressing human forms of APOE/Tau, and expose them to our r-mTBI paradigm to address these timely and under-studied interactions. We will first expose these models topharmacological manipulation of microglia using depopulation/repopulation paradigms to delineate their contribution to the APOE influence on r-mTBI pathogenesis and tau pathology. In the next part of the study, we will use an inducible APOE-KI model to genetically manipulate to delineate their contribution to the APOE influence on microglial TBI mediated neurodegeneration, tau pathology and behavioral outcome. microglia specific APOE expression transcriptomic phenotypes and ex vivo functional activities, We will finally compare TBI-dependent microglial transcriptomic responses in the presence or absence of APOE deletion in this model to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will confirm the translational relevance of our targets in r-mTBI/control autopsy cases from different APOE backgrounds. Our future work will interrogate the functional and therapeutic roles of these targets. This study is much needed as a first step in deciphering the role of APOE4 in microglia pathobiology after r-mTBI, which is currently under-investigated.

重复性轻度TBI（R-MTBI）的标志之一是慢性特征，是神经元中磷酸化tau的沉积。 tau 病变也是ADRD的主要标志特征之一。尚不清楚哪种特定分子触发器沉淀 通往这种独特的TBI相关神经退行性表型的路径。 E4等位基因是AD的主要遗传危险因素。 携带1份副本的个人对AD有2-3倍的风险，而具有2份副本的人与E3载体相比具有15倍的风险。 尽管进行了一些矛盾的研究，但E4等位基因长期与TBI之后的结果不佳有关，但起着的作用 APOE响应TBI仍然未知，需要精心设计的纵向研究。在 由于缺乏流行病学和前瞻性数据，人类仍然具有挑战性，加上TBI病因的异质性， 包括（但不限于）严重程度，年龄，合并症和TBI之后的时间，表现出极大的混乱 问题。因此，解决这个问题的最佳方法是在翻译相关，特征和控制的动物中 模型，其中关键的易感遗传因素可以靶向和表达，而纵向分析的发现可以 与人类TBI病例的有限尸检信息有关，后者在受伤后在不同的时间点死亡。 我们已经开发并表征了R-MTBI的小鼠模型，这些模型概括了人类TBI的许多特征 病理。在最近的工作中，我们暴露了人类APOE靶向的替代小鼠（APOE-TR），用于tau人性化的小鼠 （Tauki）和这些小鼠（E-TAU）的交叉与我们的R-MTBI范式，并观察到依赖TBI的PTAU病理学。从这些 我们的研究还表明，E4等位基因增强了促炎的小胶质细胞反应和Tau病理学 与E3相比，受伤的小鼠受伤。 APOE在疾病相关的小胶质细胞中被上调，这在AD大脑中已有报道。在 我们的R-MTBI模型也证实了小胶质细胞特异性APOE基因表达的增加。疾病相关 据报道，小胶质细胞可以推动AD转基因中APOE4依赖性神经变性的结果和节奏 模型；然而，对于它们在R-MTBI之后驱动APOE4介导的效果方面的贡献知之甚少。我们将解决这些 使用鼠标的未知数 表达人类形式 apoe/tau，将它们暴露于我们的R-MTBI范式以解决 这些及时且研究不足的互动。我们将首先暴露这些模型的小胶质细胞处理 使用人口减少/重新口范例来描述其对APOE对R-MTBI发病机理的影响的贡献 和tau病理学。在研究的下一部分中，我们将使用诱导的APOE-KI模型进行基因操纵 描绘他们对ApoE对小胶质细胞影响的贡献 TBI介导的神经退行性，TAU病理和行为结果。 小胶质细胞 特定的APOE表达转录组表型和 离体功能活动，我们最终将比较 在此模型中存在或不存在APOE缺失的情况下，依赖TBI的小胶质细胞转录组响应以揭示 小胶质细胞特定靶标与R-MTBI后的有利结果相关并代表新的治疗靶标。我们将 确认来自不同APOE背景的R-MTBI/控制尸检案例中我们目标的翻译相关性。我们的 未来的工作将询问这些目标的功能和治疗作用。这项研究非常需要作为第一步 在R-MTBI之后，APOE4在小胶质细胞病理生物学中的作用被解释，目前对此进行了评估。