PIP2 Discovery Could Restore Brain Blood Flow in Alzheimer's and Dementia

Reduced blood flow to the brain is considered a major factor in several types of dementia, including Alzheimer's disease. Scientists have now identified a new process that controls this circulation, which could also shed light on how it becomes disrupted.

Researchers at the University of Vermont found that a fat molecule helps keep this system in balance. In mouse models of Alzheimer's disease, disturbances to that balance caused circulation problems.

Correcting the disruption brought blood flow closer to normal, presenting a potentially encouraging new avenue for understanding and treating brain changes associated with dementia.

"This discovery is a huge step forward in our efforts to prevent dementia and neurovascular diseases," says pharmacologist Osama Harraz.

How PIP2 and Piezo1 regulate brain blood flow

Drawing on earlier work involving endothelial cells, which form the inner lining of blood vessels, the researchers focused on Piezo1, a protein that acts as a pressure 'sensor' within these cells. If this sensor becomes excessively active, it can interfere with blood flow in the brain.

After analysing brain activity in mice, the team found that a fat molecule known as PIP2 serves as a brake for Piezo1. During periods of brain-cell activity, PIP2 levels fall and Piezo1 switches on, raising blood flow to the areas that need it.

In the mouse models of Alzheimer's, however, PIP2 levels were unusually low. As a result, Piezo1 became overactive, increasing blood flow in regions where it was not needed and upsetting circulation more broadly.

Importantly, restoring PIP2 levels in the mice largely reinstated normal patterns of blood flow.

Implications for Alzheimer's disease and vascular dementia

It remains early in the effort to understand precisely how this system operates: the research was short-term and examined only mice. Nevertheless, it represents another promising line of investigation into the underlying causes of dementia.

Vascular dementia, where reduced blood flow to the brain is a major contributor, is among the most common forms of dementia and affects millions of people around the world. Problems with blood flow are also believed to contribute to Alzheimer's disease, although the harmful accumulation of toxic proteins is probably more important.

Because circulation governs the supply of oxygen and nutrients to the brain, the significance of these findings reaches beyond dementia. Preserving the proper balance is vital to ensure the brain functions correctly.

"These findings establish the foundation for a therapeutic approach for improving cerebral blood flow in conditions where Piezo1 activity is altered and could have impacts beyond brain blood flow control," write the researchers in their published paper.

Although knowledge of dementia is gradually advancing, much remains unknown about how these illnesses start and why certain people are more susceptible than others. Even for vascular dementia, the full range of factors affecting blood flow has not been established.

Research such as this helps address those unknowns by revealing the molecular components involved.

The next stage of the PIP2 research

The researchers will next investigate exactly how PIP2 interacts with Piezo1. Clarifying that relationship will be essential for regulating the system and, potentially, restoring healthy blood flow - and perhaps cognitive function as well.

"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," says Harraz.

The research has been published in PNAS.