Elucidating roles of microglial lipid droplets in neurodegeneration

阐明小胶质细胞脂滴在神经退行性变中的作用

基本信息

批准号：
10605044
负责人：
George Travis Tabor
金额：
$ 3.36万
依托单位：
WASHINGTON UNIVERSITY
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：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605044
关键词：
Acceleration Address Adipocytes Adopted Affect Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloidosis Apolipoprotein E Astrocytes Autopsy Biogenesis Biological Brain Brain region Buffers CNS degeneration Cell physiology Cells Clinical Trials Complement Coupled Cytoprotection Dementia Development Disease Disease Progression Enzymes Exhibits Fatty Acids Genes Genetic Genetic Risk Genetic Transcription Genotype Goals Human Hypoxia Inflammation Inflammatory Intervention Knock-out Knowledge Late Onset Alzheimer Disease Lipids Lipolysis Literature Membrane Microglia Mitochondria Modeling Mus Myelogenous Nerve Degeneration Neurofibrillary Tangles Neuroglia Pathogenesis Pathologic Pathway Analysis Pathway interactions Persons Phagocytes Phagocytosis Phase Phenotype Play Predisposing Factor Process Production Protein Isoforms Role Sampling Senile Plaques Shapes Stains Stress Tauopathies Therapeutic Time Tissues Toxic effect United States Variant abeta accumulation aged apolipoprotein E-3 apolipoprotein E-4 arm biomarker identification cell type cytokine density design diacylglycerol O-acyltransferase differential expression endoplasmic reticulum stress extracellular insight lipid metabolism lipidomics mouse model nervous system disorder novel pharmacologic preclinical study response targeted treatment tau Proteins tau aggregation transcriptome transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) affects approximately 6 million people in the United States and currently has no clearly-effective disease modifying therapies. AD is pathologically defined by the accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles in the brain and it is known that alterations in the activities of microglia and other non-neuronal cell types play important roles in shaping the disease course. Much of the polygenic risk for AD is derived from variants in genes expressed by microglia, specifically those involved in endolysosomal and lipid processing pathways, and microglia containing abundant lipid droplets (LD-MG) have been observed in post-mortem human AD brains. As previous interventions targeting Aβ have not yet been successful in clinical trials, the concept of modulating microglial lipid metabolism is a novel and exciting avenue being explored in preclinical studies, however we need to know more about how lipid metabolism governs microglial functional states. In mouse models of amyloidosis, microglia transition from a homeostatic to a disease-associated (DAM) transcriptional state that represents a protective, phagocytic, and plaque- compacting phenotype. While microglial activity may be beneficial in the early amyloid phase of AD, pharmacological or genetic inhibition of microglia has been shown to be protective in mouse models of tauopathy. LD-MG are observed in actively degenerating brain regions in a tauopathy mouse model, but the functions of these cells in the disease process are not currently known. To begin addressing this question, we will use FACS coupled with scRNAseq to characterize any transcriptional differences between LDhigh vs LDlow microglia isolated from 9.5 month old tauopathy mice. Given recent evidence suggesting that the LD-MG observed in aged mice have pro-inflammatory, hypo-phagocytic phenotypes, we hypothesize that the LD-MG in our tauopathy model will have similar pathway alterations and could thus be partially responsible for microglial contributions to neurodegeneration. To assess the relevance of these findings to humans, we will stain postmortem human AD brain samples for any promising mouse LD-MG markers. To elucidate the functional roles of LD-MG in the progression of tauopathy, we will utilize a new mouse model that allows for the inducible, microglial-specific knockout of the diacylglycerol acyltransferase (DGAT) enzymes, which have been demonstrated to be required for LD biogenesis in multiple biological contexts. A substantial amount of literature supports a role for lipid droplets in sequestering potentially toxic lipids and we hypothesize that crippling the ability of MG to form LDs via DGAT KO will accelerate tauopathy progression, which we will assess using a combination of immunohistochemical, scRNAseq, and lipidomic analyses. Our studies will characterize an understudied subset of microglia, increase our knowledge of the diversity of myeloid functional states, and evaluate the potential of modulating microglial lipid metabolism for the treatment of Alzheimer disease.

项目摘要/摘要阿尔茨海默氏病（AD）在美国影响约600万人，目前没有明显有效的疾病修饰疗法。 AD是通过淀粉样ββ的积累在病理上定义的（Aβ）大脑中的斑块和tau神经原纤维缠结，众所周知，活动的改变小胶质细胞和其他非神经元细胞类型在塑造疾病过程中起着重要作用。大部分 AD的多基因风险来自小胶质细胞表达的基因的变异，特别是参与的基因。内溶性溶肿和脂质加工途径，以及含有丰富脂质液滴（LD-MG）的小胶质细胞具有在验尸后人类大脑中观察到。由于先前针对Aβ的干预措施尚未在临床试验中成功，调节小胶质脂质代谢的概念是一种新颖而令人兴奋的途径在临床前研究中探讨，但是我们需要更多地了解脂质代谢如何管理小胶质功能状态。在淀粉样变性的小鼠模型中，小胶质细胞从体内稳态过渡到疾病相关（DAM）转录状态，代表保护性，吞噬和斑块压实表型。虽然小胶质细胞活性在AD的早期淀粉样蛋白阶段可能是有益的，但在小鼠模型中，已证明对小胶质细胞的药理或遗传抑制受到保护 tauopathy。 LD-MG在Tauopathy小鼠模型的主动退化大脑区域中观察到，但是这些细胞在疾病过程中的功能目前尚不清楚。为了开始解决这个问题，我们将使用与scrnaseq相结合的FACS来表征LDHIGH与Ldlow之间的任何转录差异从9.5个月大的陶氏小鼠中分离出的小胶质细胞。鉴于最近的证据表明LD-MG 在老年小鼠中观察到的具有促炎性的，低形细胞表型，我们假设LD-MG 在我们的Tauopathy模型中，模型将具有类似的途径改变，因此可能部分负责小胶质细胞对神经变性的贡献。为了评估这些发现与人类的相关性，我们将染色后人类广告脑样品，用于任何承诺小鼠LD-MG标记。阐明 LD-MG在Tauopathy的进展中的功能作用，我们将利用一种新的鼠标模型，该模型允许二酰基甘油酰基转移酶（DGAT）酶的诱导型小胶质细胞特异性敲除，这些酶已经在多种生物学环境中，LD生物发生是必需的。大量文学支持脂质液滴在隔离潜在有毒脂质中的作用，我们假设这使脂质液滴瘫痪 MG通过DGAT KO形成LD 免疫组织化学，SCRNASEQ和脂肪组分析的组合。我们的研究将表征小胶质细胞的负研究，增加了我们对髓样功能状态多样性的了解，并评估调节小胶质脂质代谢以治疗阿尔茨海默氏病的潜力。