Human antimicrobial peptide LL-37 contributes to Alzheimer’s disease progression

• Published in: Molecular psychiatry Vol. 27; no. 11; pp. 4790 - 4799
• Main Authors: Chen, Xue, Deng, Suixin, Wang, Wenchao, Castiglione, Stefania, Duan, Zilei, Luo, Lei, Cianci, Francesca, Zhang, Xiaoxue, Xu, Jianglei, Li, Hao, Zhao, Jizong, Kamau, Peter Muiruri, Zhang, Zhiye, Mwangi, James, Li, Jiali, Shu, Yousheng, Hu, Xintian, Mazzanti, Michele, Lai, Ren
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2022; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/21; 13/51; 14/19; 631/378; 631/80; 64/110; 64/60; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Antimicrobial agents; Antimicrobial peptides; Atrophy; Behavioral Sciences; Biological Psychology; Cathelicidins - metabolism; Cathelicidins - pharmacology; Chloride Channels - metabolism; Cognition; Excitotoxicity; Humans; Inflammation; Medicine; Medicine & Public Health; Mice; Microglia - metabolism; Neurodegenerative diseases; Neurofibrillary tangles; Neurosciences; Peptides; Pharmacotherapy; Phenotypes; Psychiatry; Synaptic plasticity; Ventricle (lateral); β-Amyloid
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01790-6

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.