The mechanosensitive Piezo1 channel mechanism of Alzheimer's disease and implications to development of therapeutic or early detection strategy

Lin-Hua Jiang^*Mo ZhangHuifang HouHui LiXinyang BaiHuina SongLu Wang

• Henan Medical University, Xinxiang, China

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, and the disease mechanism is complex and still remains poorly understood. AD is the leading cause of dementia and represents a major clinical challenge. Therefore, early detection and diseasemodifying therapeutics are urgently needed. Piezo1 is a mechanically-activated Ca 2+ -permeable cation channel with a key role in mechanosensing and mechano-transduction [1]. Recent studies have disclosed a critical role for the Piezo1 channel in modifying AD and, in addition, positive association of the Piezo1 channel activity in red blood cells (RBC) with early development of AD-related dementia. In this opinion piece, we summarize the recent findings and debate whether the Piezo1 channel is a feasible target for formulating strategies for modifying AD and detecting AD-related dementia in early stage. Accumulation of amyloid  peptides (Aβ) not only leads to the formation of extracellular senile plaques, one of the pathohistological hallmarks of AD, but also acts as an early disease-driving factor. The capacity of microglia to phagocytose A is severely impaired in AD, which plays a critical part in Aβ accumulation and plaque formation. In the plaques, Aβ exist in diverse species, including fibrillar A (fA) that significantly stiffs the plaques and surrounding tissues.Interestingly, the Piezo1 channel expression was upregulated in 5xFAD mice, a mouse model of Aβ-driven AD, specifically in a plaque-associated subpopulation of microglia [2].Consistently, the Piezo1 channel expression was also increased in mouse microglia cultured on fA. More importantly, exposure to fA induced Ca 2+ influx via activating the Piezo1 channel [3] and, in contrast, the Ca 2+ response in microglia evoked by the Piezo1 channel activator Yoda1 was inhibited by pre-treatment with soluble A [2], indicating A species-dependent modulation of the Piezo1 channel. Activation of the Piezo1 channel using Yoda1 stimulated microglial migration and A phagocytosis [2]. As further demonstrated in 5xFAD mice, intraperitoneal injection of Yoda1 enhanced microglial migration and clustering around the plaques and Aβ phagocytosis, alleviated Aβ accumulation and plaque formation and, most importantly, improved cognitive function, whereas deletion of microglial Piezo1 channel expression impaired microglial clustering around the plaques and Aβ internalization, leading to heightened A accumulation and plaque formation and accelerated synaptic and cognitive deficits [2,3]. Collectively, these observations provide consistent evidence to indicate that activation of the microglial Piezo1 channel by fA-enriching plaques instigates microglial migration and Aβ phagocytosis, hence limiting A accumulation and plaque formation and improving cognitive function. In other words, the microglial Piezo1 channel plays a vital role in inhibiting AD progression (Fig. 1). In addition to impaired clearance of Aβ by microglial phagocytosis, chronic and low-grade inflammation, mediated by microglia and also astrocytes, is well recognized as a vital factor in AD progression [4]. Emerging evidence points to the glial Piezo1 channels for their role in regulating the proinflammatory response of glial cells to A or lipopolysaccharide (LPS), a neurotoxin released by Gram-negative bacteria. As shown in cultured microglia, exposure to stiff A induced activation of the Piezo1 channel, and thereby promoted microglial generation of reactive oxygen species (ROS) that in turn impaired microglial viability and the capacity of phagocytosis, favouring an important role of microglial Piezo1 channel in the intricate interplays between neuroinflammation and A phagocytosis [5]. The Piezo1 channel expression was upregulated in TgF344-AD rat brains, mostly noticeable in reactive astrocytes surrounding the plaques in aged TgF344-AD rats infected with Escherichia coli [6]. As shown in cultured astrocytes, the Piezo1 channel expression was upregulated by A-conditioned microglial media, indicating requirement of microglia in upregulating the astrocytic Piezo1 channel expression [6]. LPS-evoked proinflammatory response of astrocytes was inhibited by Piezo1 channel activation [6]. Similarly, LPS-evoked proinflammatory response of microglia, or specifically generation of proinflammatory cytokines, tumour necrosis factor (TNF)-, interleukin (IL)-1 and IL-6, was inhibited by Piezo1 channel activation [7]. In microglia, such an inhibition was shown to mediate by Piezo1-mediated Ca 2+ influx-dependent suppression of LPS-induced toll-like receptor 4 (TLR4)-mediated activation of the NF-kB signalling pathway [7]. In short, Piezo1 channel activation dampens proinflammatory response of microglia (Fig. 1) and astrocytes to exposure to A/LPS, but the contribution of these Piezo1-mediated inhibitory mechanisms in AD merits further investigations. Nevertheless, these findings provide more information to endorse and expand the inhibitory role of the Piezo1 channel in AD progression. Activation of the microglial complement pathways promotes synaptic pruning, which is a wellrecognized mechanism for synaptic loss in the early stage of AD [8]. LPS-containing extracellular vesicles (EVs) released or originated from gut bacteria were detected at a higher level in AD patients than in healthy individuals [9]. LPS-containing EVs isolated from human blood (bEVs), upon injected in mice peripherally, penetrated the blood-brain-barrier (BBB) and emerged in the brain. Moreover, LPS from such bEVs sufficiently stimulated the microglial C1q-C3 complement pathway to induce synaptic pruning in mice, which was alleviated by depleting microglial Piezo1 channel expression. These observations support the notion that activation of the microglial Piezo1 channel mediates synaptic loss by EVs-carrying LPS from gut bacteria to the brain (Fig. 1). Such a finding sheds novel mechanistic light on the gut-brain axis hypothesis of AD. However, how LPS induces Piezo1 channel activation remains unclear and, furthermore, evidence for its significance in AD still awaits. It is important to notice that activation of such a microglial Piezo1 channel mechanism facilitates AD progression and thus is opposite to those described above. In addition to the role in modifying AD, emerging evidence suggests an increase in the Piezo1 channel activity in RBC and supports positive association of such increased Piezo1 channel activity with early development of AD-related dementia [10]. The activity of the Piezo1 channel expressed in RBC exerts important influences on the volume, shape and deformability of RBC, or the ability of RBC in microcirculation in the brain. A are accumulated in blood vessels and interact with RBC and, by inducing RBC aggregation, imped microcirculation, leading to cerebral amyloid angiopathy. Pre-incubation of RBC from healthy donors with A decreased plasma membrane stiffness and viscosity, resulting in higher pressure needed for Piezo1 channel activation [10]. Acute pre-incubation with A attenuated Piezo1 channel activation, indicating an inhibitory effect on the Piezo1 channel in RBC [10], similar to what described above for the effect of soluble A on microglia [2]. Exposure to Yoda1 induced similar Ca 2+ responses in RBC from both mild cognitive impairment (MCI) and AD patients, which however were significantly higher than that in RBC from healthy subjects. Yoda1-induced cell shrinkage and reduction in the cell size were also greater in RBC from MCI patients as well as AD patients as compared to that in healthy RBC, indicating upregulation of the Piezo1 expression occurs in MCI or the early stage of AD. Furthermore, interaction analysis, evaluating Piezo1-mediated Ca 2+ flux in RBC, conventional AD biomarkers, classification of patients, memory scores and magnetic resonance imaging (MRI) measurements, revealed positive association of the increase in the Piezo1 channel activity in RBC with early AD-related dementia, leading to the proposal of incorporating assessment of the RBC Piezo1 channel activity in diagnostic tests of AD is instructive in the early detection of AD-related dementia [10].In summary, recent studies have disclosed an important role for the mechanosensitive Piezo1 channel in glial cells, particularly microglia, in modifying AD via distinctive mechanisms and, in addition, positive association of an increase in the RBC Piezo1 channel activity with early development of AD-related dementia. The findings have offered novel mechanistic insights into AD. However, further researches are anticipated to gain a better understanding of the Piezo1 channel mechanism of AD and more information to inform whether the Piezo1 channel can be used as a feasible target for formulating strategies to modify AD and detect AD-related dementia in the early stage.