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

Molecular Psychiatry volume 27, pages 4790–4799 (2022)Cite this article

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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.

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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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Author notes

  1. These authors contributed equally: Xue Chen, Suixin Deng, Wenchao Wang, Stefania Castiglione, Zilei Duan.

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Xue Chen, Wenchao Wang, Zilei Duan, Lei Luo, Jianglei Xu, Peter Muiruri Kamau, Zhiye Zhang, James Mwangi, Jiali Li, Xintian Hu & Ren Lai

  2. Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai, 200032, China

    Suixin Deng, Xiaoxue Zhang & Yousheng Shu

  3. Department of Biosciences, University of Milano, Via Celoria 26, I-20133, Milano, Italy

    Stefania Castiglione, Francesca Cianci & Michele Mazzanti

  4. Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Lei Luo, Peter Muiruri Kamau, Zhiye Zhang, James Mwangi & Ren Lai

  5. Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China

    Jianglei Xu

  6. Beijing Tiantan Hospital and China National Clinical Research Center for Neurological Diseases, Capital Medical University, 119 South Fourth Ring Road West, Fengtai District, Beijing, 100071, China

    Hao Li & Jizong Zhao

  7. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Xintian Hu

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Contributions

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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The original online version of this article was revised: In the original version of this article, we found that the incorrect Golgi-Cox staining image of Clic1−/− -LL-37 group was in Figure 4G due to a data processing error. It has now been replaced. We are sorry for this oversight.

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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 27, 4790–4799 (2022). https://doi.org/10.1038/s41380-022-01790-6

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