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Human Antimicrobial Peptide LL-37 Contributes to Alzheimer's Disease Progression
论文题目: Human Antimicrobial Peptide LL-37 Contributes to Alzheimer's Disease Progression
作者: Chen, X ; Deng, SX; Wang, WC; Castiglione, S; Duan, ZL; Luo, L; Cianci, F ; Zhang, XX; Xu, JL; Li, H; Zhao, JZ ; Kamau, PM ; Zhang, ZY ; Mwangi, J ; Li, JL; Shu, YS ; Hu, XT; Mazzanti, M ; Lai, R
联系作者: rlai@mail.kiz.ac.cn
发表年度: 2022
DOI: DOI10.1038/s41380-022-01790-6
摘要: 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-β, 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
刊物名称: Molecular Psychiatry
论文出处: https://www.nature.com/articles/s41380-022-01790-6
影响因子: 13.437(2021IF)
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