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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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) 的慢性特征之一是神经元中磷酸化 tau 蛋白的沉积。牛头蛋白病变也是 ADRD 的主要标志特征之一。目前尚不清楚具体的分子触发因素是什么通向这种独特的 TBI 相关神经退行性表型的途径。 E4等位基因是AD的主要遗传风险因素；携带 1 个拷贝的个体患 AD 的风险是 E3 携带者的 2-3 倍，而携带 2 个拷贝的个体患 AD 的风险是 E3 携带者的 15 倍。尽管存在一些相互矛盾的研究，但 E4 等位基因长期以来一直被认为与 TBI 后的不良预后相关，但它所发挥的作用 APOE 对 TBI 的反应仍然未知，需要精心设计的纵向研究。进行此类研究由于缺乏流行病学和前瞻性数据，加上 TBI 病因学的异质性，人类仍然面临挑战，包括（但不限于）严重程度、年龄、合并症和 TBI 后时间，呈现出极其混乱的情况问题。因此，解决这个问题的最佳方法是在翻译相关的、良好表征和控制的动物中模型，其中可以针对和表达关键的易感遗传因素，纵向分析的结果可以与在受伤后不同时间点死亡的人类 TBI 病例的尸检信息有限有关。我们开发并表征了这种 r-mTBI 小鼠模型，它概括了人类 TBI 的许多特征病理。在最近的工作中，我们暴露了人类 APOE 靶向替代小鼠 (APOE-TR)，即 Tau 蛋白人源化小鼠 (TauKI) 并将这些小鼠 (E-Tau) 与我们的 r-mTBI 范例杂交，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，受伤的小鼠。 APOE 在疾病相关的小胶质细胞中表达上调，据报道，这种情况在 AD 大脑中。在我们的 r-mTBI 模型还证实了小胶质细胞特异性 APOE 基因表达的增加。相关疾病据报道，小胶质细胞可驱动 AD 转基因中 APOE4 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 APOE4 介导效应中的贡献却知之甚少。我们将解决这些使用小鼠模型未知表达人类的形式 APOE/Tau，并将它们暴露于我们的 r-mTBI 范式中以解决这些及时且未被充分研究的相互作用。我们将首先将这些模型暴露于小胶质细胞的药理学操作使用去种群/再种群范式来描述它们对 APOE 对 r-mTBI 发病机制影响的贡献和 tau 病理学。在研究的下一部分中，我们将使用诱导型 APOE-KI 模型来进行基因操纵描述它们对 APOE 对小胶质细胞影响的贡献 TBI 介导神经变性、tau 病理学和行为结果。小胶质细胞特定的 APOE 表达转录组表型和离体功能活动，我们最后会比较在该模型中存在或不存在 APOE 缺失的情况下，TBI 依赖性小胶质细胞转录组反应揭示小胶质细胞特异性靶点与 r-mTBI 后的良好结果相关，并代表新的治疗靶点。我们将确认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。我们的未来的工作将探讨这些靶点的功能和治疗作用。这项研究非常有必要作为第一步破译 APOE4 在 r-mTBI 后小胶质细胞病理学中的作用，目前尚在研究中。