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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease
Jin Hu1, Qiang Chen1, Hongrui Zhu2
1State 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.
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.
Insights
Alzheimer's disease microglia use Piezo1 channels to sense amyloid-β plaque stiffness, promoting plaque clearance. Blocking Piezo1 worsens Alzheimer's pathology and cognitive decline.
Area of Science:
- Neuroscience
- Cell Biology
- Biophysics
Background:
- Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques.
- The mechanical influence of Aβ plaques on brain tissue and microglial function is poorly understood.
- Microglial mechanosensing pathways in AD pathogenesis remain largely unexplored.
Purpose of the Study:
- Investigate the role of microglial mechanosensing in Alzheimer's disease.
- Determine if mechanical properties of Aβ plaques influence microglial behavior.
- Identify potential therapeutic targets for AD based on microglial mechanosensing.
Main Methods:
- Surveyed tissue stiffness in Aβ plaque-associated regions.
- Observed Piezo1 ion channel expression in microglia near Aβ plaques.
- Utilized Piezo1 knockout and pharmacological activation in 5×FAD mouse models.
- Assessed Aβ pathology and cognitive function.
Main Results:
- Aβ plaque-associated brain tissues exhibit increased stiffness.
- The mechanosensitive ion channel Piezo1 is upregulated in microglia near Aβ plaques.
- Piezo1 activation by Aβ fibril stiffness triggers microglial clustering and phagocytosis, compacting plaques.
- Loss of Piezo1 exacerbates Aβ pathology and cognitive deficits.
- Pharmacological Piezo1 activation reduces Aβ burden and improves cognition in AD mice.
Conclusions:
- Microglial Piezo1 acts as a mechanosensor for Aβ fibril stiffness.
- Piezo1-mediated microglial responses are crucial for mitigating Aβ pathology.
- Targeting microglial Piezo1 offers a potential therapeutic strategy for Alzheimer's disease.
