Regulation of LDAM by autopahgy in the aging brain

衰老大脑中自噬对 LDAM 的调节

基本信息

批准号：
10900994
负责人：
MARTA M LIPINSKI
金额：
$ 66.04万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10900994
关键词：
Acceleration Acute Adipose tissue Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Arterial Fatty Streak Attenuated Autophagocytosis Behavior assessment Biochemical Brain Catabolism Cells Cellular biology Characteristics Cholesterol Cognition Complement Complex Data Defect Development Disease Encephalitis Environment Epidemiology Flow Cytometry Functional disorder Gene Expression Profile Generations Genes Genetic Transcription Homeostasis Human Hyperactivity Immunofluorescence Immunologic Inflammation Inflammatory Link Lipids LoxP-flanked allele Lysosomes Macrophage Methods Microglia Modernization Mus Myelin Nerve Degeneration Neurodegenerative Disorders Outcome Pathologic Pathology Pathway interactions Phagocytes Phagocytosis Phagocytosis Induction Population Predisposition Process Property Proteins Proteomics Regulation Role Testing Time Tissues Transgenic Mice age related aged aging brain analytical tool brain cell cell growth regulation cell type extracellular functional improvement in vitro Assay in vivo inhibition of autophagy lipid metabolism lipidomics multidisciplinary multiple omics neuroinflammation proteostasis single-cell RNA sequencing uptake

Acceleration Acute Adipose tissue Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Arterial Fatty Streak Attenuated Autophagocytosis Behavior assessment Biochemical Brain Catabolism Cells Cellular biology Characteristics Cholesterol Cognition Complement Complex Data Defect Development Disease Encephalitis Environment Epidemiology Flow Cytometry Functional disorder Gene Expression Profile Generations Genes Genetic Transcription Homeostasis Human Hyperactivity Immunofluorescence Immunologic Inflammation Inflammatory Link Lipids LoxP-flanked allele Lysosomes Macrophage Methods Microglia Modernization Mus Myelin Nerve Degeneration Neurodegenerative Disorders Outcome Pathologic Pathology Pathway interactions Phagocytes Phagocytosis Phagocytosis Induction Population Predisposition Process Property Proteins Proteomics Regulation Role Testing Time Tissues Transgenic Mice age related aged aging brain analytical tool brain cell cell growth regulation cell type extracellular functional improvement in vitro Assay in vivo inhibition of autophagy lipid metabolism lipidomics multidisciplinary multiple omics neuroinflammation proteostasis single-cell RNA sequencing uptake

展开

项目摘要

During brain aging and in neurodegenerative diseases such as Alzheimer’s disease (AD), microglia lose their homeostatic properties, gradually becoming activated and pro-inflammatory. While the transcriptional changes occurring in aging- and neurodegenerative disease-associated microglial populations have been characterized, many questions regarding their generation remain. Because of prevalent branched cells and presence of cholesterol-rich myelin, CNS has overall higher levels of lipids than most other tissues except the adipose. As the resident phagocytic cells of the brain, microglia are responsible for clearing dead cells and cellular debris, including lipids. Recent data indicate that phagocytosis of certain lipids, in particular cholesterol, can cause lysosomal disruption. This has been documented in tissues high in cholesterol such as atherosclerotic plaques, where accumulation of lipid droplets in foam macrophages is associated with lysosomal dysfunction. Lipid droplet associated microglia (LDAM) are also observed in the aged mouse, aged human and AD patient brains and have properties and transcriptional profiles resembling foam macrophages, however the mechanisms contributing to their formation are not fully understood. Lysosomal dysfunction causes inhibition of autophagy, a lysosome-dependent catabolic pathway, which has been linked to brain aging, AD, and other neurodegenerative diseases. Recent data demonstrate that in addition to its well-established role in protein homeostasis, autophagy participates in regulation of cellular lipid catabolism and inflammation. We hypothesize that myelin lipid phagocytosis by microglia leads to lysosomal and autophagy inhibition, which in turn exacerbates defects in lipid metabolism and accelerates formation of LDAM. In AIM 1 we will determine the mechanisms how lipid phagocytosis leads to inhibition of microglial autophagy in the aging brain. In AIM 2 we will identify the autophagic mechanisms contributing to accumulation of lipid droplets and formation of LDAM and other pathological microglial populations. In AIM 3 we will determine whether increasing autophagy can attenuate LDAM formation and microglial inflammation associated with brain aging. We expect our data will identify the interaction between microglial lipid metabolism and autophagy pathways as important contributor to generation of age- and neurodegeneration-associated microglial population and demonstrate that increasing autophagy can attenuate this process and improve function of aged microglia.

在大脑衰老和神经退行性疾病（例如阿尔茨海默氏病）（AD）中，小胶质细胞失去了稳态特性，逐渐被激活和促炎。而转录变化发生在衰老和神经退行性疾病相关的小胶质细胞种群中，已经表征了关于他们这一代的许多问题仍然存在。由于普遍的分支细胞和富含胆固醇的髓磷脂的存在，CNS总体上具有更高的水平除脂肪外，大多数其他组织的脂质。作为居民的大脑吞噬细胞，小胶质细胞是负责清除死细胞和细胞碎屑，包括脂质。最近的数据表明某些脂质，尤其是胆固醇会导致溶酶体破坏。这已在组织中记录高胆固醇，例如动脉粥样硬化斑块，其中脂肪滴在泡沫巨噬细胞中的积累与溶酶体功能障碍有关。还观察到脂质液滴相关的小胶质细胞（LDAM）老鼠，年龄的人类和广告患者大脑，具有类似的特性和转录曲线泡沫巨噬细胞，但是造成其形成的机制尚未完全理解。溶酶体功能障碍会导致抑制自噬，这是一种溶酶体依赖性分解代谢途径，其具有与大脑衰老，AD和其他神经退行性疾病有关。最近的数据表明，此外鉴于其在蛋白质稳态中的良好作用，自噬参与细胞脂质分解代谢和炎症。我们假设小胶质细胞的髓磷脂脂质吞噬作用会导致溶酶体和自噬抑制作用又加剧了脂质代谢中的缺陷，并加速了LDAM的形成。在目标1中我们将确定脂质吞噬作用如何导致衰老中的小胶质细胞自噬的机制脑。在AIM 2中，我们将确定有助于脂质液滴积累的自噬机制 LDAM和其他病理小胶质细胞种群的形成。在AIM 3中，我们将确定是否增加自噬可以减弱与脑衰老相关的LDAM形成和小胶质细胞注射。我们期望我们的数据将确定小胶质脂质代谢和自噬途径之间的相互作用是重要的年龄和神经退行性相关的小胶质细胞的产生贡献者，并证明这一点自噬的增加可以减弱这一过程并改善老化的小胶质细胞的功能。