期刊
MOLECULAR PSYCHIATRY
卷 27, 期 11, 页码 4790-4799出版社
SPRINGERNATURE
DOI: 10.1038/s41380-022-01790-6
关键词
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资金
- National Key R&D Program of China [2018YFA0801403]
- National Natural Science Foundation of China [31930015, 81941014, 31800901]
- Chinese Academy of Science [XDB31000000, SAJC202103, KFJ-BRP-008-003]
- Yunnan Province [2019-YT-053,, 202002AA100007, 202003AD150008]
- Chongqing Municipal Education Commission [HZ2021020]
- Kunming Science and Technology Bureau [2023SCP001]
- Yunnan Province Grant [2019FB127]
- China Postdoctoral Science Foundation [2021T140126]
- Key-Area Research and Development Program of Guangdong Province [2019B030335001]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB32060200, XDA16020900, XDB29050301]
- National Science and Technology Innovation 2030 Major Program [2021ZD0200900]
- Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province [2018FB052, 202001AT070130, 2021000055, 202101AY070001-001]
- Yunnan Key Research and Development Program [202003AD150009]
- Yunnan Fundamental Research Projects [202201AT070139]
- National Science Foundation of China [32130044, 32000680]
This study reveals that the antimicrobial peptide LL-37 promotes the membrane translocation and integration of CLIC1, leading to microglial hyperactivation and neuroinflammation in Alzheimer's disease. The findings suggest that LL-37 may act as an endogenous agonist of CLIC1, driving the progression of AD.
As a prime mover in Alzheimer's disease (AD), microglial activation requires membrane translocation, integration, and activation of the metamorphic protein chloride intracellular channel 1 (CLIC1), which is primarily cytoplasmic under physiological conditions. However, the formation and activation mechanisms of functional CLIC1 are unknown. Here, we found that the human antimicrobial peptide (AMP) LL-37 promoted CLIC1 membrane translocation and integration. It also activates CLIC1 to cause microglial hyperactivation, neuroinflammation, and excitotoxicity. In mouse and monkey models, LL-37 caused significant pathological phenotypes linked to AD, including elevated amyloid-beta, increased neurofibrillary tangles, enhanced neuronal death and brain atrophy, enlargement of lateral ventricles, and impairment of synaptic plasticity and cognition, while Clic1 knockout and blockade of LL-37-CLIC1 interactions inhibited these phenotypes. Given AD's association with infection and that overloading AMP may exacerbate AD, this study suggests that LL-37, which is up-regulated upon infection, may be a driving force behind AD by acting as an endogenous agonist of CLIC1.
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