Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome
Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome
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DOI：
10.4161/auto.29647
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发表时间：
2014-10-01
期刊：
影响因子：
13.3
通讯作者：
Yoon, Seung-Yong
中科院分区：
文献类型：
--
作者：
Cho, Mi-Hyang;Cho, Kwangmin;Yoon, Seung-Yong
阿尔茨海默病(AD)的重要病理特征是β-淀粉样蛋白(Aβ)的积聚和由此引起的炎症。小胶质细胞是大脑中的主要免疫细胞，通过溶酶体系统摄取和降解细胞外的Aβ纤维。自噬是一种降解天然细胞成分的分解代谢过程，然而，自噬在小胶质细胞降解Aβ中的作用及其对AD的影响尚不清楚。在这里，我们通过小胶质细胞特异的ATG7基因敲除小鼠和细胞培养，展示了自噬在小胶质细胞清除细胞外Aβ纤维和调节Aβ诱导的NLRP3(NLR家族，包含3个吡喃结构域)炎症小体中的新作用。我们在小胶质细胞培养中发现，Aβ通过OPTN/optineurin与MAP1LC3B-II相互作用，并通过PRKAA1途径介导的自噬过程被降解。我们预计，增强小胶质细胞自噬可能是治疗AD的一种有前途的新策略。
Accumulation of beta-amyloid (A beta) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular A beta fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in A beta degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular A beta fibrils by microglia and in the regulation of the A beta-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that A beta interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.