Regulation of LDAM by autopahgy in the aging brain

在大脑老化和阿尔茨海默病(AD)等神经退行性疾病中，小胶质细胞失去了 动态平衡特性，逐渐变得活跃和促炎。而转录的变化 发生在衰老和神经退行性疾病相关的小胶质细胞群体中已经被表征， 关于他们这一代人的许多问题仍然存在。 由于常见的分支细胞和富含胆固醇的髓鞘的存在，中枢神经系统的水平总体较高 比除脂肪以外的大多数其他组织的脂肪含量高。作为大脑的常驻吞噬细胞，小胶质细胞 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 某些脂类，特别是胆固醇，会引起溶酶体的破坏。这已经在组织中被记录下来了 高胆固醇，如动脉粥样硬化斑块，泡沫巨噬细胞中积累的脂滴 与溶酶体功能障碍有关。脂滴相关的小胶质细胞(LDAM)也可在 衰老的小鼠、衰老的人类和AD患者的大脑，具有类似于 然而，泡沫巨噬细胞的形成机制尚不完全清楚。 溶酶体功能障碍导致自噬抑制，自噬是一种溶酶体依赖的分解代谢途径，具有 与脑老化、阿尔茨海默病和其他神经退行性疾病有关。最近的数据表明，此外 由于自噬在蛋白质动态平衡中的作用已经确立，它还参与了细胞脂质分解代谢的调节。 和炎症。我们假设小胶质细胞吞噬髓鞘脂类导致溶酶体和自噬。 抑制，进而加剧脂质代谢缺陷，加速LDAM的形成。在目标1中我们 将确定在衰老过程中脂质吞噬如何导致抑制小胶质细胞自噬的机制 大脑。在目标2中，我们将确定导致脂滴积累的自噬机制和 形成LDAM和其他病理性小胶质细胞群。在目标3中，我们将确定是否增加 自噬可以减少LDAM的形成和与脑老化相关的小胶质细胞炎症。我们预计 我们的数据将确认小胶质细胞脂代谢和自噬途径之间的相互作用是重要的。 对年龄和神经退行性变相关的小胶质细胞群体的生成有贡献，并证明 增加自噬可以减弱这一过程，改善衰老小胶质细胞的功能。

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.