Abstract
Background. Alzheimer’s disease (AD) pathogenesis extends beyond biochemical alterations to include biomechanical dysfunction. Brain tissue stiffening, vascular shear stress changes, and impaired fluid dynamics characterize the AD brain. PIEZO1, a mechanosensitive ion channel, translates these mechanical cues into pathological signaling across neural cells.
Objective: This review synthesizes current evidence on PIEZO1 in AD, proposing an integrated mechanobiological model in which PIEZO1 links brain mechanical remodeling to cellular and molecular pathologies. Methods. A comprehensive literature search of PubMed and Scopus was conducted to identify studies on PIEZO1 expression, activation, and downstream signaling in the context of AD. Molecular, cellular, and animal studies involving microglia, astrocytes, neurons, endothelial cells, and pericytes were critically evaluated to construct a unified model of mechanotransductive dysfunction.
Results. PIEZO1 dysfunction affects multiple systems in AD. Vascular impairment reduces shear-stress responses, causing hypoperfusion and blood-brain barrier leakage. Glymphatic clearance is compromised via reduced vascular pulsatility, weakening Aβ removal. Microglial PIEZO1 senses Aβ stiffness to promote early phagocytosis, yet chronic activation drives neuroinflammation; astrocytic PIEZO1 contributes to reactive gliosis. In neurons, abnormal PIEZO1 signaling disrupts synaptic plasticity. This establishes a self-reinforcing cycle: tissue stiffening further activates PIEZO1, exacerbating pathology.
Conclusion. PIEZO1 is a central mechanotransducer, integrating biomechanical alterations into AD pathogenesis. PIEZO1 emerges as a high-value, yet complex, therapeutic target in AD. Realizing its potential will depend on the development of precision 'mechanopharmacology'—interventions that are not only cell- and stage-specific but also capable of fine-tuning channel activity rather than simply activating or inhibiting it. Future studies must prioritize the development of targeted modulators and a deeper understanding of the temporal dynamics of PIEZO1 signaling across the disease continuum.
Keywords: PIEZO1, mechanobiology, Alzheimer’s disease, neurovascular unit, tissue stiffness, calcium signaling.
For citation:Khaled A. Abdel-Sater. The mechanobiology of Alzheimer’s disease: PIEZO1 as the nexus of brain stiffening and neurodegeneration. Clinical review for general practice. 2026; 7 (3): 11–14. DOI: 10.47407/kr2026.7.3.00785
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