Alzheimer's disease is associated with increased production of amyloid-β (Aβ). These are protein deposits due to accumulation and aggregation of peptides formed by cutting of the amyloid precursor protein (APP) by the enzymes β- and γ-secretase (see Fig. 2.17 in my book on neurodegeneration). Aβ-plaques are often surrounded by microglial cells that are closely associated with the plaque surface. The consequences of Aβ-peptide aggregation in the form of plaques are significant in many, but not all, affected individuals: they reduce blood flow by contracting capillary pericytes, impair the blood-brain barrier, disrupt synaptic functions, and activate glial cells. Their reduction in the aging brain is therefore of great importance.
Aβ-peptides are normally degraded enzymatically or transported away via the glymphatic system and the blood-brain barrier. Furthermore, plaques are internalized and phagocytosed by microglial cells. In a recent paper published in the journal Neuron, Hu and colleagues describe a novel mechanism by which microglia can recognize plaques. Crucial, apparently, is the increased stiffness of the tissue surrounding the plaques. Selective upregulation of a mechanosensitive ion channel (Piezo1) in the plasma membrane of microglial cells stimulates cell migration and phagocytosis via an increase in calcium influx.
Piezo1 is activated after deformation of the plasma membrane by shear stress or also by an altered membrane tension. The authors of the paper demonstrated in an animal model of Alzheimer's disease, the 5xFAD mouse, that local changes in stiffness occur in the vicinity of Aβ-plaques, which are sensed via Piezo1. This leads to a positive feedback loop that upregulates Piezo1 expression, increasing sensitivity to mechanically triggered ionic currents in microglia.
To compare the stiffness of Aβ-plaque-associated tissues with normal tissues in brain slices from 5xFAD mice, the authors used atomic force microscopy (AFM). These experiments showed that tissue stiffness was much greater in Aβ plaque-associated tissues than in non-Aβ plaque-associated tissues, presumably due to the presence of stiff Aβ aggregates inside the plaques.
Interestingly, amyloid burden and behavioral deficits are exacerbated in mice that can no longer produce Piezo1 in microglia. In these animals, microglia accumulation near plaques and Aβ internalization are reduced. In contrast, when a blood-brain barrier-crossing and selective small-molecule activator of Piezo1 (YODA1) is injected, Aβ uptake into cells increases and the density of Aβ plaques decreases. Simultaneously, the memory of treated 5×FAD mice is also improved in behavioral tests. To confirm a microglia-mediated effect, the authors demonstrated that it was absent when YODA1 was administered to Piezo1 knockout mice.
Taken together, the present results suggest that microglial mechanosensitivity is mediated by Piezo1 and likely plays a critical role in mediating the microglial response to Aβ accumulation, thereby regulating AD progression.
These observations are also supported by a recent paper in the Journal of Neuroinflammation by Jäntti and colleagues, who demonstrated a similar relationship between Piezo1 activation and Aβ clearance in 5×FAD mice. Here, Aβ-oligomers were shown to decrease the calcium response to YODA1-mediated Piezo1 activation in cultured induced pluripotent stem cell-derived microglial cells.
Both papers provide exciting insight into the function of microglial mechanosensitivity in Alzheimer's disease. However, evidence that the described effects play a role in older animals and in human Alzheimer's pathology is still pending. In any case, there seems to be an upregulation of Piezo1 not only in mice but also in the microglia of Alzheimer's patients. Finally, the negative consequences of chronic Piezo1 activation would also need to be investigated, as it may promote synapse and myelin degradation.
References:
Davis H, Attwell D (2023) Plaque attack: microglia have hard feelings toward amyloid-β. Neuron 111:1
Hu J, Chen Q, Zhu H, ..., Zhang L, Mo W (2023) Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease. Neuron 111:15
Jäntti H, Sitnikova V, Ishchenko Y, ... , Malm T (2022) Microglial amyloid beta clearance is driven by PIEZO1 channels. Journal of Neuroinflammation 19:147
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