For more than 20 years, scientists have known that people with high blood pressure, diabetes, high cholesterol or obesity are more likely to develop Alzheimer’s disease.
The disorders can all affect the brain, damage blood vessels and lead to strokes. But the link between brain vascular disease and Alzheimer’s disease has remained elusive, despite researchers’ best efforts.
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 cerebrovascular disease-induced changes in FMNL2 activity 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 high blood pressure, diabetes, obesity or heart disease.
“Not only do we have a gene, we also have a potential mechanism,” says lead author Richard Mayeux, MD, Chair of Neurology at Columbia and New York-Presbyterian/Columbia University Irving Medical Center. “People have been trying to figure this out for a number of decades and I think we have our foot in the door now. We think other genes must be involved, and we’ve only scratched the surface. »
Mayeux and his colleagues found FMNL2 in a genome-wide hunt aimed at discovering genes linked to both vascular risk factors and Alzheimer’s disease. The research included 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. At this point, Caghan Kizil, PhD, a visiting associate professor at Columbia, put his expertise to good use with zebrafish as a model organism for Alzheimer’s disease.
FMNL2 and the blood-brain barrier
“We had this gene, FMNL2, that 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 act at the blood-brain barrier, where brain cells meet the vasculature. »
The blood-brain barrier is a semi-permeable, tightly controlled boundary between capillaries and brain tissue that serves to defend against pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, form and maintain the structure of the blood-brain barrier by forming a protective covering around blood vessels. This astrocyte covering must break down 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 envelope, which retracted its grip around the blood vessel once toxic proteins were injected into the brain, presumably to allow clearance. When Kizil and his colleagues blocked FMNL2 from functioning, this retraction did not occur, preventing amyloid from being cleared from the brain. The same process was later confirmed using transgenic mice with Alzheimer’s disease.
The same process can also take place in the human brain. Researchers examined postmortem 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 – which controls its astrocytes – and promotes the removal 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 investigating additional genes potentially involved in the interaction between Alzheimer’s disease and cerebrovascular diseases, which together with FMNL2 could provide future approaches for drug development.
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