Regulation of LDAM by autopahgy in the aging brain

在脑老化和神经退行性疾病如阿尔茨海默病（AD）中，小胶质细胞失去其功能。 体内平衡特性，逐渐被激活和促炎。当转录变化 发生在与衰老和神经变性疾病相关的小胶质细胞群体中， 关于他们这一代人的许多问题仍然存在。 由于普遍存在的分支细胞和富含胆固醇的髓鞘的存在，CNS具有总体较高的水平， 除了脂肪外，大多数组织的脂肪含量都比其他组织高。作为大脑的常驻吞噬细胞，小胶质细胞是 负责清除死亡细胞和细胞碎片，包括脂质。最近的数据表明， 某些脂质特别是胆固醇可引起溶酶体破坏。这已经在组织中被记录下来 高胆固醇，如动脉粥样硬化斑块，其中脂滴在泡沫巨噬细胞中积聚 与溶酶体功能障碍有关脂滴相关的小胶质细胞（LDAM）也观察到在 老年小鼠、老年人和AD患者脑，并且具有类似于 泡沫巨噬细胞，然而，促进其形成的机制尚未完全理解。 溶酶体功能障碍导致自噬抑制，自噬是一种溶酶体依赖性分解代谢途径， 与大脑老化、AD和其他神经退行性疾病有关。最近的数据显示，此外， 自噬除了在蛋白质稳态中的作用外，还参与细胞脂质过氧化的调节， 和炎症。我们假设小胶质细胞对髓鞘脂质的吞噬作用导致溶酶体和自噬 抑制，这反过来又加剧了脂质代谢的缺陷，并加速LDAM的形成。在AIM 1中， 将确定衰老过程中脂质吞噬作用如何抑制小胶质细胞自噬的机制 个脑袋在AIM 2中，我们将确定有助于脂滴积累的自噬机制， LDAM和其他病理性小胶质细胞群的形成。在AIM 3中，我们将确定是否增加 自噬可以减弱LDAM形成和与脑老化相关的小胶质细胞炎症。我们预计 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是重要的 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老化小胶质细胞的功能。

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.