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Updated: Sep 8, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglial amyloid beta clearance is driven by PIEZO1 channels
Henna Jäntti1, Valeriia Sitnikova1, Yevheniia Ishchenko1,2
1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
Background:
Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.
Methods:
Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.
Results:
We show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.
Conclusion:
These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.
Insights
Activating PIEZO1 channels in microglia enhances their function, improving amyloid beta (Aβ) clearance in Alzheimer's disease (AD). This offers a potential new therapeutic strategy for AD by targeting microglial mechanoreceptors.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are brain immune cells crucial for homeostasis, sensing pathology and eliminating threats.
- In Alzheimer's disease (AD), impaired amyloid beta (Aβ) clearance by microglia contributes to plaque accumulation, particularly in late-onset AD.
- While neurochemical pathways regulating microglia are studied, their mechanical receptors remain largely unexplored.
Purpose of the Study:
- To investigate the role of the mechanotransduction ion channel PIEZO1 in microglial function related to Alzheimer's disease.
- To determine if activating PIEZO1 can enhance microglial Aβ clearance and improve AD-related pathology.
Main Methods:
- Investigated PIEZO1 expression and function in human and mouse microglia.
- Utilized Yoda1, a PIEZO1 agonist, on human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) to assess cell survival, metabolism, phagocytosis, and lysosomal activity.
- Administered Yoda1 to 5xFAD mice to evaluate in vivo effects on microglial Iba1 expression and Aβ pathology.
- Analyzed PIEZO1 gene expression in human and mouse AD datasets.
Main Results:
- PIEZO1 is expressed and functional in microglia, orchestrating Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity.
- Yoda1 activation of PIEZO1 improved microglial phagocytosis and Aβ clearance in both human and mouse AD models.
- PIEZO1 expression correlated with a distinct microglial transcriptional phenotype in AD, impacting cellular metabolism.
Conclusions:
- Compromised microglial function in AD can be improved by activating PIEZO1 channels, leading to reduced Aβ burden.
- Pharmacological targeting of PIEZO1 mechanoreceptors in microglia presents a novel therapeutic avenue for Alzheimer's disease.
