Human antimicrobial peptide LL-37 contributes to Alzheimer's disease progression. Mol Psychiatry, 2022.

Title: Human antimicrobial peptide LL-37 contributes to Alzheimer's disease progression

Author:Chen X, Deng S, Wang W, Castiglione S, Duan Z, Luo L, Cianci F, Zhang X, Xu J, Li H, Zhao J, Kamau PM, Zhang Z, Mwangi J, Li J, Shu Y, Hu X, Mazzanti M, Lai R.

Publication Name: Mol Psychiatry

Pub Year: 2022

Doi:10.1038/s41380-022-01790-6

IF: 13.437

Abstract: 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.