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.
This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
OBJECTIVE Identifying metabolic factors associated with critical disease can help to improve management of patients hospitalized for coronavirus disease 2019 (COVID-19). High triglycerides and low HDL levels characterize the atherogenic dyslipidemia closely related to insulin resistance and diabetes. We examined associations of atherogenic dyslipidemia detected on admission with outcome of COVID-19 during hospitalization. RESEARCH DESIGN AND METHODS We retrospectively analyzed clinical reports of 118 consecutive patients hospitalized for COVID-19 in Rome, Italy, between March and May 2020. Clinical characteristics, inflammation markers, and glucose and lipid metabolism parameters at admission were collected. Critical disease was defined as in-hospital death or need for endotracheal intubation. Associations were tested using logistic regression analysis. RESULTS Patients with critical COVID-19 (n = 43) were significantly older than those with noncritical disease (n = 75) and presented higher levels of fasting glucose, triglycerides, C-reactive protein, interleukin-6, procalcitonin, and d-dimer (P < 0.01 for all), whereas HDL levels were lower (P = 0.003). Atherogenic dyslipidemia was more frequent in patients with critical COVID-19 (46 vs. 24%, P = 0.011), as well as diabetes (37 vs. 19%, P = 0.026), and significantly associated with death or intubation (odds ratio 2.53 [95% CI 1.16–6.32], P = 0.018). Triglycerides were significantly associated with selected inflammatory biomarkers (P < 0.05 for all) and poorer outcome of COVID-19 during hospitalization in both the overall population and the subgroup with atherogenic dyslipidemia. CONCLUSIONS Atherogenic dyslipidemia detected on admission can be associated with critical in-hospital course of COVID-19. Further investigations are needed to elucidate the hypothetical role of insulin resistance and related lipid abnormalities in severe acute respiratory syndrome coronavirus 2 pathogenesis. Assessment of lipid profile should be encouraged in patients hospitalized for COVID-19.
Background: Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs. Methods: We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke.
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