Comerota Michele, Gedam Manasee, Xiong Wen, Jin Feng, Deng Lisheng, Wang Meng, Wang Jin, Zheng Hui
Baylor College of Medicine.
Janelia.
Res Sq. 2023 Jan 20:rs.3.rs-2484513. doi: 10.21203/rs.3.rs-2484513/v1.
Emerging evidence implicates impaired microglia function and dysregulation of lipid metabolism in Alzheimer's disease (AD). Oleoylethanolamide (OEA), an endogenous lipid and PPARα agonist, has been shown to promote longevity in through regulation of lysosome-to-nucleus signaling and cellular metabolism. Using a stable OEA analog, KDS-5104, we found that OEA-PPARα signaling promotes TFEB lysosomal activity independent of mTORC1 and upregulates cell-surface receptor CD36, leading to enhanced microglial Aβ uptake and clearance. These are associated with the suppression of LPS-induced lipid droplet accumulation and inflammasome activation. Chronic treatment of the 5xFAD mice with KDS-5104 restored dysregulated profiles, reduced reactive gliosis and Aβ pathology and rescued cognitive impairments. Together, our study provides support that augmenting OEA-mediated lipid signaling may offer therapeutic benefit against aging and AD through modulating lipid metabolism and microglia phagocytosis and clearance.
新出现的证据表明，小胶质细胞功能受损和脂质代谢失调与阿尔茨海默病（AD）有关。油酰乙醇胺（OEA）是一种内源性脂质和PPARα激动剂，已被证明可通过调节溶酶体到细胞核的信号传导和细胞代谢来延长寿命。使用稳定的OEA类似物KDS-5104，我们发现OEA-PPARα信号传导促进TFEB溶酶体活性，独立于mTORC1，并上调细胞表面受体CD36，导致小胶质细胞Aβ摄取和清除增强。这些与抑制LPS诱导的脂滴积累和炎性小体激活有关。用KDS-5104对5xFAD小鼠进行长期治疗可恢复失调的状态，减少反应性胶质增生和Aβ病理，并挽救认知障碍。总之，我们的研究支持增强OEA介导的脂质信号传导可能通过调节脂质代谢以及小胶质细胞吞噬和清除作用，为对抗衰老和AD提供治疗益处。
