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

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.

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Fig. 1: LL-37 is up-regulated in AD brains and promotes CLIC1 expression and membrane translocation.
Fig. 2: LL-37 activates CLIC1 channel to cause neuroglial and neuronal toxicity.
Fig. 3: LL-37 enhances spiking responses and AHP in CA1 pyramidal cells through CLIC1 channel.
Fig. 4: LL-37 induces AD-like pathological phenotypes in mice by activating CLIC1.
Fig. 5: LL-37 induces AD-like pathological phenotypes in rhesus monkeys.
Fig. 6: Human antimicrobial peptide LL-37 that is up-regulated upon infection and inflammation promotes Alzheimer’s disease by promoting the expression, membrane translocation and activation of CLIC1 to induce neuroinflammation.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

This work was supported by National Key R&D Program of China (2018YFA0801403), the National Natural Science Foundation of China (31930015), Chinese Academy of Science (XDB31000000, SAJC202103 and KFJ-BRP-008-003), KC Wong Education Foundation, Yunnan Province Grant (2019-YT-053, 202002AA100007 and 202003AD150008) and Chongqing Municipal Education Commission (HZ2021020) and Kunming Science and Technology Bureau (2023SCP001) to RL, and Yunnan Province Grant (2019FB127) to ZD, National Science Foundation of China (32130044 to YS and 32000680 to SD) and China Postdoctoral Science Foundation (2021T140126) to SD. Key-Area Research and Development Program of Guangdong Province (2019B030335001), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB32060200), the National Science and Technology Innovation 2030 Major Program (2021ZD0200900), the National Natural Science Foundation of China (81941014 and 31800901), the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province (2018FB052, 202001AT070130, 2021000055, 202101AY070001-001), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020900, XDB29050301), Yunnan Key Research and Development Program (202003AD150009), Yunnan Fundamental Research Projects (202201AT070139).

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XC, SD, WW, SC and ZD conducted the majority of experiments including Immunohistochemical analysis, western blot, confocal microscopy, fluorescence assay, electrophysiological and animal assays. XZ contributed to the brain slices recordings. RL, MM, YS and XH prepared the manuscript. XC, SD, WW, SC, ZD, FC, XZ, LL, PK, ZZ, JM, JL, HL, and JZ participated in data analysis and manuscript writing. XH, YS. MM and RL conceived and supervised the project.

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Correspondence to Yousheng Shu, Xintian Hu, Michele Mazzanti or Ren Lai.

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Chen, X., Deng, S., Wang, W. et al. Human antimicrobial peptide LL-37 contributes to Alzheimer’s disease progression. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01790-6

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