Hu J, Chen Q, Zhu H, Hou L, Liu W, Yang Q, Shen H, Chai G, Zhang B, Chen S, Cai Z, Wu C, Hong F, Li H, Chen S, Xiao N, Wang ZX, Zhang X, Wang B, Zhang L, Mo W. Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease. Neuron. 2023 Jan 4;111(1):15-29.e8. Epub 2022 Nov 10 PubMed.

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  1. These studies elegantly demonstrate that microglia are able to detect and respond to changes in tissue stiffness via the Piezo1 mechanoreceptor, and that this mechanism is essential for their detection and response to plaques. Furthermore, deletion of Piezo1 from microglia impairs their response to plaques, phenocopying Trem2 deficiency, and exacerbating plaque-induced damage. Importantly, this work further reinforces the protective effects of microglia in the early stages of disease, and their direct link to neuronal health and damage. It will be important to further evaluate this at later disease stages, and also in the context of tau pathology.

    The overlap between published Trem2 KO studies and the Piezo1 KO data are intriguing—it suggests that microglia require both detection of changes in tissue stiffness as well as TREM2 ligands to react to plaques. Notably, Piezo1 KO did not prevent the induction of TREM2-dependent, disease-associated microglia (DAM) gene induction, suggesting some non-overlapping roles, yet microglia in intact animals with reduced Piezo1 expression appeared to increase TREM2-dependent DAM gene expression.

    Both studies highlight the dramatic effects that the Piezo1 agonist Yoda1 has on microglial responses to plaques—increasing clustering, and decreasing plaque burden, dystrophic neurites, and cognitive impairments, etc. It will be intriguing to see how Piezo1 agonists develop and what effects they may have in other diseases and at different disease states.

    View all comments by Kim Green

  2. I think these two PIEZO1 papers are very interesting. They add to the evidence that a protective function of microglia is to wall off plaques to limit Aβ access to cellular structures vulnerable to tau aggregation.

    I wonder over what spatial scale PIEZO1 can detect changes in stiffness. Hu et al. report increased local changes in tissue stiffness near plaques, which are tens of microns in diameter. They also report that a suspension of synthetic Aβ fibrils, perhaps microns long, but presumably only nanometers in diameter, can provoke a PIEZO1-dependent microglial response. Can an individual fibril at the furthest edges of a plaque activate PIEZO1, or does one need a thick “mesh” that could influence the total stiffness of the surrounding parenchyma? Further, would a different (non-Aβ) extracellular amyloid have the same effect if it increased tissue stiffness, or is there something specific about Aβ fibrils?

    These will be interesting questions to address.

    View all comments by Andrew Stern

  3. Ever since its discovery in 2010, the function of Piezo1 has been widely characterized in different tissues and cell types, in both physiological and pathological contexts. However, little was known regarding its role in microglia.

    Here, Jin Hu et al. showed that amyloid plaques in mouse AD brains can increase tissue stiffness, and microglia sense and respond to tissue stiffness via Piezo1-mediated calcium signaling. They observed that 5xFAD mice with microglial-specific Piezo1 depletion sustained higher plaque load and more severe memory deficit, which was likely due to the impaired microglia phagocytosis; Yoda1 (a highly specific Piezo1 activator) administration nicely ameliorated AD pathology in 5xFAD mice, but not in Piezo1 KO 5xFAD mice. Transcriptomic analysis revealed that genes related to cytoskeleton dynamics were downregulated in Piezo1 KO microglia, which explained why they were less capable of engulfing and compacting Aβ plaques.

    The study from Jäntti et al. utilized iPSC-derived microglia-like cells and demonstrated that Yoda1 treatment increased microglia migration, phagocytosis, and lysosomal function. Similarly, they also apply Yoda1 in 5xFAD mice and observed a reduction of plaque burden.

    These discoveries uncover a novel aspect of how microglia sense Aβ plaques. Previous research in the field has focused on how innate sensing receptors (such as Trem2 and Clec7a) and phagocytic receptors (Mer, Axl, Tyro3) help to sense and engulf Aβ. These two papers showed that despite its biochemical properties, Aβ plaques can also provide mechanical stimuli to trigger microglial phagocytosis through an entirely different machinery.

    One of the remaining questions about these Piezo1-expressing microglia is where they fit in with the current microglia transcriptional landscape. Although Piezo1+ microglia are more enriched in plaque-associated regions (Figure 2 in Hu et al.) and have a more phagocytic and activated phenotype, they don’t seem to acquire disease-associated microglia (DAM) signatures. Jäntti et al. even showed that Piezo1 mRNA level negatively correlated with DAM marker genes. It would be interesting to further characterize their transcriptional signatures.

    It will also be interesting to know how Piezo1 expression is regulated in vivo—is it triggered by Aβ fibrils (as shown in the in vitro experiments by Hu et al.) or by other cues in the microenvironment? Another intriguing point to follow up is the interplay between mechanosensory signaling and innate receptor/phagocytic receptor signaling pathways during microglia activation (i.e., do they have a synergetic or redundant role), since calcium signaling is broadly involved in multiple pathways. These studies definitely open up a lot of avenues for further investigation.

    View all comments by Marco Colonna

  4. I read through both these papers and the findings are exciting. Both studies indicated that PIEZO1 ion channels on microglia are a new pharmacological target that can help in the removal of Aβ aggregates. These works showed that activation of PIEZO1 channels by a small molecule called Yoda1 reduced aggregate population. At a more fundamental level, these publications show that cell mechanics affect brain function and that we need to explore this issue in greater detail to better understand brain pathologies.

    View all comments by Philip Gottlieb

  5. Piezo 1 research has gained interest lately, especially in connection with Alzheimer’s disease pathological hallmarks, such as plaque formation and the ensuing changes in the stiffness in the tissue surrounding plaques. These changes in stiffness induce the activation and alteration in behavior of resident brain immune cells—the microglia. The role of microglia in Alzheimer’s disease (AD) has been studied by many researchers over the last decades. The recent findings deciphering the importance of Piezo1 in specific processes characteristic of microglia—the engulfment of Aβ plaques and phagocytosis of Aβ—implicate Piezo1 as a necessary player in the defense system maintained by microglia.

    Of particular importance is the potential to regulate Piezo1 with the agonist Yoda1, which has direct implications for the number, morphology, and distribution of Aβ plaques, resulting in changes in cognitive capacity in the 5xFAD AD transgenic mouse model. These two recent studies analyzed the effects of Yoda 1 in the presymptomatic and symptomatic phase of the disease, obtaining encouraging results in both cases. The presymptomatic phase of AD is particularly important because it is assumed that the disease starts in people several decades before the onset of the symptoms. It is possible that current therapies are so ineffective because by the time symptoms emerge the disease is so developed that the treatments are futile. It would be interesting to compare the effects of Piezo1 activation (or loss) on microglia in particular phases of the disease. The 5xFAD mouse aggressively produces Aβ under the Thy1 promoter, and the upregulation of Piezo1 may have even stronger effects in milder, more humanized AD mouse models, such as APP knock-ins. Although Yoda 1 effectively activated Piezo1 and diminished Aβ plaque burden when delivered into the brain, either intraperitoneally or through cerebroventricular infusion, the broader effects of activated Piezo1 warrant further investigations.

    Piezo1 function is regulated via force, from lipids or through the lipid composition of the membrane, including incorporated polyunsaturated fatty acids (PUFAs), which can affect Piezo1 by altering mechanosensitive properties of the cell. While PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and the immune response, Piezo1 activity was implicated in similar modulations of microglia behavior (for review see Ivkovic et al., 2022). It will be interesting to investigate the alterations of Piezo1 activity in microglia (in parallel with microglial behavior) under the treatment with PUFAs. Importantly, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1.

    References:

    Ivkovic S, Major T, Mitic M, Loncarevic-Vasiljkovic N, Jovic M, Adzic M. Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease. Life Sci. 2022 May 15;297:120470. Epub 2022 Mar 10 PubMed.

    View all comments by Sanja Ivkovic

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