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Mechanotransduction Activates Microglia and Impairs Phagocytosis in Stiff Amyloid-β Plaques
Yulin Liu1,2, Junjie Zhang1,2, Yuxiang Zhao1,2
1The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.
Abstract:
In Alzheimer's disease (AD), microglia are activated by mechanical and biochemical cues in the amyloid-β (Aβ) plaque-associated microenvironment, causing neuroinflammation. While the impact of Aβ stiffness on microglial activation and the dynamic interplay between inflammation and phagocytosis remain unclear. Here, an in vitro Aβ plaque-associated microglia microenvironment model is built and investigated how the stiffness of Aβ plaques triggers microglial activation via the PIEZO1 mechanotransduction pathway. Scanning electrochemical microscopy and scanning ion conductance microscopy are employed to in situ monitor reactive oxygen species release, membrane permeability, and phagocytic activity of microglia. It is found that Aβ stiffness drives early microglial activation, forming an oxidative-stressed microenvironment that impairs the membrane integrity of microglia. And the antioxidant-resveratrol effectively improves the phagocytosis dysfunction of the impaired microglia. This work reveals the complex interplay among mechanical cues, neuroinflammation, and phagocytic dysfunction in microglia and suggests potential therapeutic strategies targeting microglial dysfunction in AD.
Insights
Alzheimer's disease plaque stiffness activates microglia via PIEZO1, causing inflammation and impairing phagocytosis. Antioxidant resveratrol may restore microglial function in Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Biomaterials
Background:
- Microglia activation in Alzheimer's disease (AD) is influenced by amyloid-β (Aβ) plaques.
- The specific role of Aβ plaque stiffness in microglial activation and its impact on neuroinflammation and phagocytosis are not fully understood.
Purpose of the Study:
- To investigate how Aβ plaque stiffness triggers microglial activation through the PIEZO1 mechanotransduction pathway.
- To explore the interplay between mechanical cues, neuroinflammation, and phagocytic dysfunction in microglia within an in vitro AD model.
Main Methods:
- Development of an in vitro model simulating the Aβ plaque-associated microglia microenvironment.
- Utilized scanning electrochemical microscopy and scanning ion conductance microscopy for in situ monitoring of microglial activity.
- Assessed reactive oxygen species release, membrane permeability, and phagocytic activity.
Main Results:
- Aβ stiffness was found to drive early microglial activation, leading to an oxidative-stressed microenvironment.
- Impaired microglial membrane integrity and phagocytic dysfunction were observed due to Aβ stiffness.
- The antioxidant resveratrol demonstrated efficacy in improving the phagocytosis of impaired microglia.
Conclusions:
- Aβ plaque stiffness is a critical factor in initiating microglial activation and subsequent neuroinflammation in AD.
- Microglial dysfunction, characterized by impaired phagocytosis, is linked to Aβ stiffness and oxidative stress.
- Targeting microglial dysfunction, potentially with agents like resveratrol, offers a promising therapeutic strategy for AD.
