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

TY - JOUR

T1 - Human antimicrobial peptide LL-37 contributes to Alzheimer’s disease progression

AU - Chen, Xue

AU - Deng, Suixin

AU - Wang, Wenchao

AU - Castiglione, Stefania

AU - Duan, Zilei

AU - Luo, Lei

AU - Cianci, Francesca

AU - Zhang, Xiaoxue

AU - Xu, Jianglei

AU - Li, Hao

AU - Zhao, Jizong

AU - Kamau, Peter Muiruri

AU - Zhang, Zhiye

AU - Mwangi, James

AU - Li, Jiali

AU - Shu, Yousheng

AU - Hu, Xintian

AU - Mazzanti, Michele

AU - Lai, Ren

N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85138531363

U2 - 10.1038/s41380-022-01790-6

DO - 10.1038/s41380-022-01790-6

M3 - Article

C2 - 36138130

SN - 1359-4184

VL - 27

SP - 4790

EP - 4799

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 11

ER -