Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease

Jin, Haixia; Chen, Qiang; Zhu, Hongrui; Hou, Lichao; Liu, Wei; Yang, Qihua; Shen, Huidan; Chai, Guolin; Zhang, Boxin; Chen, Shaoxuan; Cai, Zhiyu; Wu, Chongxin; Hong, Fan; Li, Hongda; Chen, Sifang; Xiao, Naian; Wang, Zhanxiang; Zhang, Xueqin; Wang, Bo; Zhang, Liang; Mo, Wei

doi:10.1016/j.neuron.2022.10.021

Cited by 65 publications

(53 citation statements)

References 77 publications

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“…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). Furthermore, in AD mice, depletion of Piezo1 expression reduced clustering of microglial cells at amyloid plaques and, importantly, treatment with Yoda1 stimulated phagocytosis of Aβ by microglial cells and improved cognitive function (Hu et al, 2022).…”

Section: Implications Of Piezo1 Channel Inhibition Of Microglial Pro-...supporting

confidence: 75%

“…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). Furthermore, in AD mice, depletion of Piezo1 expression reduced clustering of microglial cells at amyloid plaques and, importantly, treatment with Yoda1 stimulated phagocytosis of Aβ by microglial cells and improved cognitive function (Hu et al, 2022). These results are consistent with our findings, and strongly implicate the Piezo1 channel as an important mechanism regulating microglial cell functions that are critical to the physiological function and pathogenesis of the CNS.…”

Section: Implications Of Piezo1 Channel Inhibition Of Microglial Pro-...mentioning

confidence: 95%

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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

Malko

Jia

Wood

et al. 2022

Glia

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Microglial cells are crucial in maintaining central nervous system (CNS) homeostasis and mediating CNS disease pathogenesis. Increasing evidence supports that alterations in the mechanical properties of CNS microenvironments influence glial cell phenotypes, but the mechanisms regulating microglial cell function remain elusive.Here, we examined the mechanosensitive Piezo1 channel in microglial cells, particularly, how Piezo1 channel activation regulates pro-inflammatory activation and production of pro-inflammatory cytokines, using BV2 and primary microglial cells.Piezo1 expression in microglial cells was detected both at mRNA and protein levels.Application of Piezo1 channel activator Yoda1 induced Ca 2+ flux to increase intracellular Ca 2+ concentration that was reduced by treatment with ruthenium red, a Piezo1 inhibitor, or Piezo1-specific siRNA, supporting that Piezo1 functions as a cell surface Ca 2+ -permeable channel. Priming with lipopolysaccharide (LPS) induced microglial cell activation and production of TNF-α and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-κB. LPS-induced activation of NF-κB, but not ERK and p38, was inhibited by treatment with Yoda1. Yoda1-induced inhibition was blunted by siRNA-mediated depletion of Piezo1 expression and, furthermore, treatment with BAPTA-AM to prevent intracellular Ca 2+ increase. Collectively, our results support that Piezo1 channel activation downregulates the pro-inflammatory function of microglial cells, especially production of TNF-α and IL-6, by initiating intracellular Ca 2+ signaling to inhibit the NF-κB inflammatory signaling pathway. These findings reveal Piezo1 channel activation as a previously unrecognized mechanism regulating microglial cell function, raising an interesting perspective on targeting this molecular mechanism to alleviate neuroinflammation and associated CNS pathologies.

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Section: Implications Of Piezo1 Channel Inhibition Of Microglial Pro-...supporting

confidence: 75%

Section: Implications Of Piezo1 Channel Inhibition Of Microglial Pro-...mentioning

confidence: 95%

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

Malko

Jia

Wood

et al. 2022

Glia

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“…One of the possible applications for migraine research would be an injection of FM1-43 followed by the triggering of a migraine attack with trinitroglycerin [ 29 ] or optogenetics/the KCl-induced phenomenon of cortical depolarizations as a model of migraine with aura [ 30 , 31 ]. Alternatively, FM1-43 could be co-administered with Yoda1, which has been shown to be safe and effective for in vivo administration [ 32 ]. Successful previous activations of Piezo receptors in the meninges or other parts of the trigeminal nociceptive system in vivo could then be detected postmortem.…”

Section: Discussionmentioning

confidence: 99%

FM1-43 Dye Memorizes Piezo1 Activation in the Trigeminal Nociceptive System Implicated in Migraine Pain

Pietra¹,

Mikhailov²,

Giniatullin³

2023

IJMS

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It has been proposed that mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons, but the mechanosensitivity of satellite glial cells (SGCs) supporting neuronal sensitization has not been tested before. Moreover, tools to monitor previous Piezo1 activation are not available. Therefore, by using live calcium imaging with Fluo-4 AM and labeling with FM1-43 dye, we explored a new strategy to identify Piezo channels’ activity in mouse trigeminal neurons, SGCs, and isolated meninges. The specific Piezo1 agonist Yoda1 induced calcium transients in both neurons and SGCs, suggesting the functional expression of Piezo1 channels in both types of cells. In Piezo1-transfected HEK cells, FM1-43 produced only a transient fluorescent response, whereas co-application with Yoda1 provided higher transient signals and a remarkable long-lasting FM1-43 ‘tail response’. A similar Piezo1-related FM1-43 trapping was observed in neurons and SGCs. The non-specific Piezo channel blocker, Gadolinium, inhibited the transient peak, confirming the involvement of Piezo1 receptors. Finally, FM1-43 labeling demonstrated previous activity in meningeal tissues 3.5 h after Yoda1 washout. Our data indicated that trigeminal neurons and SGCs express functional Piezo channels, and their activation provides sustained labeling with FM1-43. This long-lasting labelling can be used to monitor the ongoing and previous activation of Piezo1 channels in the trigeminal nociceptive system, which is implicated in migraine pain.

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“…More interestingly, cells can probe the rigid and exogenous pathological fibril by membrane receptor and trigger fibril degradation for protection. A very recent study reveals that mechanosensitive ion channel—Piezo1 on the microglial membrane can sense the stiffness of Aβ fibril to promote phagocytosis and clearance of toxic Aβ fibrils by microglia [ 97 ] (Figure 4C).…”

Section: Structure and Function Relationship Of Amyloid Fibrilmentioning

confidence: 99%

“…Reprinted from ref. [97] with permission from Elsevier. (D) EYFP-labeled virions (green) were colocalized with semen that was stained with Proteostat dye (red).…”

Section: Mechanical and Surface Charge-mediated Activitymentioning

confidence: 99%

Protein amyloid aggregate: Structure and function

Sun

et al. 2023

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Protein amyloid aggregation has been widely observed to occur and plays important roles in both physiological processes and pathological diseases. Remarkably, amyloid aggregates assembled by native proteins gain a variety of different biological activities, which cannot be adopted by the unassembled protein alone. Thus, it is important to investigate the molecular basis of self‐assembly of protein amyloid aggregates and how the aggregated protein structure determines its function. In the review, we firstly introduce our structural knowledge on how different amyloid proteins undergo conformational transition and assemble into amyloid aggregate, with the main focus on amyloid fibril, which is the major species of amyloid aggregate. Then, we elaborate how different structures of amyloid fibrils enable them to fulfill highly diverse functions in either physiological or pathological condition. Furthermore, we discuss the structural polymorph which is a very unique feature of amyloid fibril, and its implication in understanding the structure‐function relationship of amyloid fibrils. Finally, we point out the importance of applying and integrating new approaches for deepening the structure‐function study of amyloid fibrils and highlight the potential of designing amyloid fibril‐based functional bio‐nanomaterials for application.

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Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease

Cited by 65 publications

References 77 publications

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

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

FM1-43 Dye Memorizes Piezo1 Activation in the Trigeminal Nociceptive System Implicated in Migraine Pain

Protein amyloid aggregate: Structure and function

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Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease

Cited by 65 publications

References 77 publications

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

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

FM1-43 Dye Memorizes Piezo1 Activation in the Trigeminal Nociceptive System Implicated in Migraine Pain

Protein amyloid aggregate: Structure and function

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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

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