Microglial amyloid beta clearance is driven by PIEZO1 channels

Abstract

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.

The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia

“… 11 , 12 , 13 , 14 One issue requiring resolution is that Jantti et al. report Yoda1 to promote microglial migration, 53 in apparent contradiction to our findings. To somewhat mimic the physiological environment of microglial migration, we adopted a transwell assay, with cells in the upper chamber and chemoattractant in the lower chamber, giving the assay a 3D aspect.…”

Piezo1 channel‐mediated Ca2+ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells

“…For example, in 5xFAD AD mice, treatment with Yoda1 reduced amyloid plaques in the brain, in conjunction with increased localization of microglial cells in the close vicinity of the plaque (Jantti et al, 2022). As shown in the same study, Piezo1 channel-mediated Ca 2+ signaling in human microglia-like cells derived from inducible pluripotent stem cells was altered by exposure to Aβ 42 , the major neurotoxic amyloid peptide species, which is consistent with the notion that the Piezo1 channel is a previously unrecognized mechanism regulating microglial cell function (Jantti et al, 2022). Another very recent study has demonstrated increased Piezo1 protein expression in microglial cells surrounding amyloid plaques in both 5xFAD mice and human AD patients (Hu et al, 2022).…”

“…Emerging evidence from recent studies indicates a potential role for the Piezo1 channel in microglial cells in alleviating the amyloid plaque burden in AD models. For example, in 5xFAD AD mice, treatment with Yoda1 reduced amyloid plaques in the brain, in conjunction with increased localization of microglial cells in the close vicinity of the plaque (Jantti et al, 2022). As shown in the same study, Piezo1 channel-mediated Ca 2+ signaling in human microglia-like cells derived from inducible pluripotent stem cells was altered by exposure to Aβ 42 , the major neurotoxic amyloid peptide species, which is consistent with the notion that the Piezo1 channel is a previously unrecognized mechanism regulating microglial cell function (Jantti et al, 2022).…”

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

“…Two pairs of previously established PSEN1 ΔE9 mutant and isogenic control human-derived iPSC lines [ 9 ] and two control lines from non-related human individuals [ 13 ] were used in this study ( Table 1 ). The use of the cells was approved by the committee on Research Ethics of Northern Savo Hospital District (license nr.…”