Research highlights a potential therapeutic strategy for vascular dementia

A possible new treatment for impaired brain blood flow and related dementias is on the horizon. Research by scientists at the University of Vermont Robert Larner, M.D. College of Medicine provides novel insights into the mechanisms that regulate brain blood flow and highlight a potential therapeutic strategy to correct vascular dysfunction. Their preclinical findings, published December 22 in Proceedings of the National Academy of Sciences, suggest that adding a missing phospholipid back into a person's circulatory system could restore normal brain blood flow and reduce symptoms of dementia.

"This discovery is a huge step forward in our efforts to prevent dementia and neurovascular diseases," says principal investigator Osama Harraz, Ph.D., assistant professor of pharmacology at Larner College of Medicine. "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."

Alzheimer's disease and related dementias affect 50 million people around the world and numbers are rising, placing immense burdens on families and health care systems. Research deciphers the role of proteins, inflammation, neural activity, and brain cell dysfunction.

Research in the Harraz lab focused on the control of cerebral blood flow and vascular signaling and the role of Piezo1, a protein that lives on the membranes of cells lining the blood vessels, in controlling brain blood flow. Named for the Greek word for "pressure," Piezo1 is a sensor of frictional forces as the blood moves through the brain vasculature. Previous studies showed that Piezo1 activity is altered in carriers of Piezo1 gene variations.

Findings from this new study, "PIP₂ Corrects an Endothelial Piezo1 Channelopathy" provide novel insights into how Piezo1 affects cerebral blood flow and shows that diseases such as Alzheimer's disease are associated with increased vascular Piezo1 activity. Harraz's team investigated a phospholipid in brain cell membranes called PIP₂. This phospholipid is vital for cell signaling and ion channel regulation-a complex process where cells control the opening and closing of protein pores. The researchers found that PIP₂ is a natural inhibitor of Piezo1; when PIP₂ levels drop, Piezo1 becomes overactive, which disturbs the brain's blood flow. They tested adding PIP₂ back into the system, which suppressed Piezo1 and restored normal blood flow. The study suggests that boosting PIP₂ could become a new treatment strategy to restore normal blood flow and enhance brain function. 

Further investigation will focus on defining how PIP₂ interacts with Piezo1, including whether it directly binds specific protein regions or alters the surrounding membrane environment to restrain pore opening. Future studies will also examine how disease-associated reductions in PIP₂ disrupt this regulatory brake, leading to sustained Piezo1 overactivity and impaired cerebral blood flow. Clarifying these mechanisms will be essential for refining PIP₂-based or Piezo1-targeted therapeutic strategies to restore healthy neurovascular function in dementia and related vascular disorders.