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

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.

在大脑衰老和阿尔茨海默病 (AD) 等神经退行性疾病中，小胶质细胞会失去其活性稳态特性，逐渐变得激活和促炎症，同时转录发生变化。发生在与衰老和神经退行性疾病相关的小胶质细胞群体中的现象已得到表征，关于他们这一代人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，中枢神经系统总体上具有较高的水平作为大脑的常驻吞噬细胞，小胶质细胞比大多数其他组织含有更多的脂质。负责清除死亡细胞和细胞碎片，包括脂质。最近的数据表明，吞噬作用。某些脂质，特别是胆固醇，可以引起组织中的溶酶体破坏。胆固醇含量高，例如动脉粥样硬化斑块，泡沫巨噬细胞中脂滴积聚还观察到与溶酶体功能障碍有关的脂滴相关小胶质细胞（LDAM）。老年小鼠、老年人类和 AD 患者大脑的特性和转录谱类似于然而，泡沫巨噬细胞的形成机制尚不完全清楚。溶酶体功能障碍会导致自噬的抑制，自噬是一种溶酶体依赖性分解代谢途径，最近的数据表明，与大脑衰老、AD 和其他神经退行性疾病有关。由于其在蛋白质稳态中的明确作用，自噬参与细胞脂质分解代谢的调节我们认为小胶质细胞的髓鞘脂质吞噬作用会导致溶酶体和自噬。抑制，进而恶化脂质代谢缺陷并加速 LDAM 的形成。将确定脂质吞噬作用如何导致衰老过程中小胶质细胞自噬抑制的机制在 AIM 2 中，我们将确定导致脂滴积累的自噬机制和在 AIM 3 中，我们将确定 LDAM 和其他病理性小胶质细胞群体的形成是否增加。我们预计自噬可以减弱 LDAM 的形成和与大脑衰老相关的小胶质细胞炎症。我们的数据将确定小胶质细胞脂质代谢和自噬途径之间的相互作用非常重要有助于年龄和神经退行性变相关的小胶质细胞群体的产生，并证明增加自噬可以减弱这一过程并改善衰老小胶质细胞的功能。