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）的标志性慢性特征之一是磷酸化tau在神经元中的沉积。Tau 病变也是ADRD的主要标志性特征之一。目前还不清楚是什么特定的分子触发物 这一独特的TBI相关神经退行性表型的途径。E4等位基因是AD的主要遗传危险因素; 与E3携带者相比，携带1个拷贝的个体具有2-3倍的AD风险，而携带2个拷贝的个体具有15倍的AD风险。 尽管有一些相互矛盾的研究，E4等位基因长期以来一直与TBI后的不良结局相关，但其所起的作用 APOE在TBI中的作用尚不清楚，需要设计良好的纵向研究。开展此类研究， 由于缺乏流行病学和前瞻性数据，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后时间， 问题.因此，解决这一问题的最佳方法是在预防相关的，良好的表征和控制的动物 模型，其中关键的易感遗传因素可以靶向和表达，纵向分析的结果可以 这可能与在受伤后不同时间点死亡的TBI病例的尸检信息有限有关。 我们已经开发并表征了这种r-mTBI的小鼠模型，其概括了人类TBI的许多特征 病理在最近的工作中，我们暴露了人APOE-targeted replacement mice（APOE-TR）， （TauKI）和这些小鼠的杂交（E-Tau）与我们的r-mTBI范例，并观察TBI依赖性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性小胶质细胞反应和Tau病理学。 与E3相比，APOE在疾病相关的小胶质细胞中上调，这在AD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。相关的疾病 据报道，小胶质细胞驱动AD转基因小鼠中APOE 4依赖性神经变性的结果和速度。 模型;然而，关于它们在r-mTBI后驱动APOE 4介导的效应中的贡献知之甚少。我们将解决这些问题 使用小鼠模型的未知数 表达人类的 APOE/Tau，并将其暴露于我们的r-mTBI范式，以解决 这些及时而又未被充分研究的互动。我们首先将这些模型暴露于小胶质细胞的药理学操作 使用去增殖/再增殖模式来描述它们对APOE对r-mTBI发病机制的影响 和tau病理学。在下一部分的研究中，我们将使用诱导型APOE-KI模型进行基因操作， 描述它们对APOE影响小胶质细胞的作用， TBI介导的神经变性、tau病理学和行为结果。 小胶质 特异性APOE表达转录组学表型， 离体功能活动，我们将最终比较 在该模型中，在存在或不存在APOE缺失的情况下，TBI依赖性小胶质细胞转录组学反应揭示了 小胶质细胞特异性靶点与r-mTBI后的有利结果相关，并代表新的治疗靶点。我们将 证实了我们的目标在来自不同APOE背景的r-mTBI/对照尸检病例中的翻译相关性。我们 未来的工作将探讨这些靶点的功能和治疗作用。这项研究非常需要作为第一步， 破译APOE 4在r-mTBI后小胶质细胞病理生物学中的作用，目前正在研究中。