2. Academic Validation
  3. Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease

Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease

  • Neuron. 2022 Nov 8;S0896-6273(22)00954-0. doi: 10.1016/j.neuron.2022.10.021.
Jin Hu 1,  Qiang Chen 2,  Hongrui Zhu 3,  Lichao Hou 4,  Wei Liu 2,  Qihua Yang 2,  Huidan Shen 5,  Guolin Chai 2,  Boxin Zhang 2,  Shaoxuan Chen 2,  Zhiyu Cai 2,  Chongxin Wu 2,  Fan Hong 2,  Hongda Li 2,  Sifang Chen 6,  Naian Xiao 6,  Zhan-Xiang Wang 6,  Xueqin Zhang 7,  Bo Wang 2,  Liang Zhang 8,  Wei Mo 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Neuroscience, the First Affiliated Hospital, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. Electronic address: jinhu@xmu.edu.cn.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Neuroscience, the First Affiliated Hospital, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 3 Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 4 Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Neuroscience, the First Affiliated Hospital, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China; Department of Anesthesiology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 6 Department of Neurosurgery, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 7 Department of Obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 8 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Neuroscience, the First Affiliated Hospital, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. Electronic address: lzhangxmu@xmu.edu.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Neuroscience, the First Affiliated Hospital, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. Electronic address: wmo@xmu.edu.cn.
PMID: 36368316 DOI: 10.1016/j.neuron.2022.10.021
Abstract

The pathology of Alzheimer's disease (AD) is featured with extracellular Amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced CA2+ influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.

Keywords

Alzheimer’s disease; Aβ plaque; Piezo1; microglial mechanosensor.

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