UVM Study Identifies Piezo1–PIP2 Interaction As A Potential Treatment Pathway For Vascular Dementia

BURLINGTON, Vt. — Researchers at the University of Vermont report new laboratory evidence that a mechanosensitive protein called Piezo1 may be overactive in models of Alzheimer’s disease and other cerebrovascular disorders, and that restoring levels of a naturally occurring brain phospholipid, PIP2, can normalize Piezo1 activity.

The study, led in part by Osama Harraz, Ph.D., an assistant professor of pharmacology at the UVM Larner College of Medicine, used mouse models designed to mimic Alzheimer’s-related and vascular forms of cognitive impairment. The team observed elevated Piezo1 activity in diseased models compared with healthy controls, a change that could impair cerebral blood flow regulation.

“We are uncovering the complex mechanisms of these devastating conditions, and now we can begin to think about how to translate this biology into therapies,” the researchers quote Harraz as saying.

What the researchers found

In the experimental models, supplementing PIP2—a phospholipid found naturally in cell membranes—restored Piezo1 activity toward normal levels. Conversely, reducing PIP2 was associated with increased Piezo1 activation, suggesting a reciprocal relationship in which PIP2 scarcity may drive abnormal Piezo1 behavior.

Mechanism and limitations

The authors do not yet identify the precise molecular mechanism linking PIP2 and Piezo1, but they propose several hypotheses and plan further experiments to clarify how the two molecules interact. Importantly, these results were obtained in mouse models and in laboratory experiments; translation to humans will require extensive additional research, including safety and efficacy testing.

Implications

Harraz and colleagues suggest that interventions that normalize endothelial Piezo1 function—potentially by modulating PIP2 levels or related signaling pathways—could open new avenues for treating vascular contributions to cognitive impairment and Alzheimer’s disease. The team also notes these findings could have relevance beyond cerebral blood flow.

The full paper, titled PIP2 Corrects An Endothelial Piezo1 Channelopathy, is published in the Proceedings of the National Academy of Sciences (PNAS) and is available on the journal’s website.

Takeaway: This study identifies a novel molecular interaction that may contribute to impaired brain blood flow in disease models and highlights a potential target for future therapeutic development, while underscoring that further work is needed before clinical applications are possible.