Regulation of LDAM by autopahgy in the aging brain

衰老大脑中自噬对 LDAM 的调节

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' 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

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.

在大脑老化和神经退行性疾病，如阿尔茨海默病（AD）中，小胶质细胞失去了它们的