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Microglia are the resident macrophages of the central nervous system (CNS) that control brain development, maintain neural environments, respond to injuries, and regulate neuroinflammation. Despite their significant impact on various physiological and pathological processes across mammalian biology, there remains a notable gap in our understanding of how microglia perceive and transmit mechanical signals in both normal and diseased states. Recent studies have revealed that microglia possess the ability to detect changes in the mechanical properties of their environment, such as alterations in stiffness or pressure. These changes may occur during development, aging, or in pathological conditions such as trauma or neurodegenerative diseases. This review will discuss microglial Piezo1 mechanosensitive channels as potential therapeutic targets for Alzheimer's disease (AD). The structure, function, and modulation of Piezo1 will be discussed, as well as its role in facilitating microglial clearance of misfolded amyloid-b (Ab) proteins implicated in the pathology of AD. [ABSTRACT FROM AUTHOR]

Piezo1 mechanosensitive ion channel (MSC) plays a significant role in human physiology. Despite several research on the function and expression of Piezo1 in the nervous system, its electrophysiological properties in neuroinflammatory astrocytes remain unknown. We tested whether astrocytic neuroinflammatory state regulates Piezo1 using electrical recordings, calcium imaging, and wound healing assays on cultured astrocytes. In this study, we determined whether neuroinflammatory condition regulates astrocytic Piezo1 currents in astrocytes. First, we performed electrophysiological recordings on the mouse cerebellum astrocytes (C8-S) under lipopolysaccharide (LPS)-induced neuroinflammatory condition. We found that LPS treatment significantly increased MSC currents in C8-S. The half-maximal pressure of LPS treated MSC currents was left-shifted but the slope sensitivity was not altered by LPS treatment. LPS-induced increase of MSC currents were further augmented by Piezo1 agonist, Yoda1 but were normalized by Piezo1 inhibitor, GsMTx4. Furthermore, silencing Piezo1 in LPS treated C8-S normalized not only MSC currents but also calcium influx and cell migration velocity. Together, our results show that LPS sensitized Piezo1 channel in C8-S astrocytes. These findings will suggest that astrocytic Piezo1 is a determinant of neuroinflammation pathogenesis and may in turn become the foundation of further research into curing several neuronal illnesses and injury related inflammation of neuronal cells. [ABSTRACT FROM AUTHOR]

Chronic pain is the most common neurological disorder of HIV patients. Multiple neuropathologies were identified in the pain pathway. Among them is the prominent astrocytic reaction (also know an astrogliosis). However, the pathogenic role and mechanism of the astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain development induced by a key neurotoxic HIV protein gp120 and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. Ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization in the spinal dorsal horn. We demonstrated that conditional knockout of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also hyperalgesia and neural circuit polarization. Furthermore, we found that the astrogliosis promoted expression of hyperalgesia and NCP via IL-1β regulated by a Wnt5a-ROR2-MMP2 axis. Our results shed light on the role and mechanism of astrogliosis in the pathogenesis of HIV-associated pain. [ABSTRACT FROM AUTHOR]