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Missing link between Alzheimer’s and vascular diseases found? –ScienceDaily

For more than 20 years, scientists have known that people with hypertension, diabetes, high cholesterol or obesity are more likely to develop Alzheimer’s disease.

The conditions can all affect the brain, damage blood vessels and lead to strokes. But the link between vascular diseases of the brain and Alzheimer’s disease has remained unexplained despite the intense efforts of researchers.

Now, a study by researchers at Columbia University’s Vagelos College of Physicians and Surgeons has uncovered a possible mechanism. The study found that a gene called FMNL2 links cerebrovascular disease and Alzheimer’s disease and suggests that changes in FMNL2 activity caused by cerebrovascular disease prevent efficient removal of toxic proteins from the brain, ultimately leading to Alzheimer’s disease.

This discovery could lead to a way to prevent Alzheimer’s disease in people with hypertension, diabetes, obesity or heart disease.

“Not only do we have a gene, but we have a potential mechanism,” says lead author Richard Mayeux, MD, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical Center. “People have been trying to figure this out for a few decades, and I think we have our foot in the door now. We think there must be other genes involved and we’ve just scratched the surface.”

Mayeux and his colleagues found FMNL2 in a genome-wide hunt designed to discover genes associated with both vascular risk factors and Alzheimer’s disease. The research involved five groups of patients representing different ethnic groups.

One gene, FMNL2, stood out in the analysis. But what role he could possibly play was unclear. That’s when Caghan Kizil, PhD, a visiting associate professor at Columbia, put his expertise with zebrafish to good use as a model organism for Alzheimer’s disease.

FMNL2 and the blood-brain barrier

“We had this gene, FMNL2, which was at the interface between Alzheimer’s disease in the brain and cerebrovascular risk factors,” says Kizil. “So we came up with the idea that FMNL2 might work in the blood-brain barrier, where brain cells meet the vasculature.”

The blood-brain barrier is a semi-permeable, highly controlled boundary between capillaries and brain tissue that serves as a defense against pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, make up and maintain the structure of the blood-brain barrier by forming a protective sheath around the blood vessel. This astrocyte sheath must loosen to remove toxic amyloid, the protein aggregates that build up in the brain and lead to Alzheimer’s disease.

The zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow clearance. When Kizil and his colleagues blocked the function of FMNL2, this retraction did not occur, preventing the clearance of amyloid from the brain. The same process was later confirmed using transgenic mice with Alzheimer’s disease.

The same process can also occur in the human brain. The researchers studied post-mortem human brains and found increased expression of FMNL2 in people with Alzheimer’s disease, as well as disruption of the blood-brain barrier and retraction of astrocytes.

Based on these findings, the researchers propose that FMNL2 opens the blood-brain barrier – controlling its astrocytes – and promotes the clearance of extracellular aggregates from the brain. And this cerebrovascular disease, by interacting with FMNL2, reduces the clearance of amyloid in the brain.

The team is currently studying other genes that may be involved in the interaction between Alzheimer’s disease and cerebrovascular disease, which together with FMNL2 could provide future approaches for drug development.