Researchers may have found the missing link between Alzheimer’s and vascular disease

summary: A new study reports that the FMNL2 gene links cerebrovascular disease and Alzheimer’s disease. Changes in activity in FMNL2 resulting from cerebral vascular diseases prevent effective cleaning of toxic proteins in the brain, leading to the development of Alzheimer’s disease.

source: Columbia University

For more than 20 years, scientists have known that people with high blood pressure, diabetes, high cholesterol, or obesity have a higher likelihood of developing Alzheimer’s disease.

All conditions can affect the brain, damaging blood vessels and leading to strokes. But the link between vascular disease in the brain and Alzheimer’s disease has remained unexplained despite the intense efforts of researchers.

Now, a study was published in Acta Neuropathologic And it’s led by researchers at Columbia University’s Vagelos College of Physicians and Surgeons, who discovered a potential mechanism.

The study found that a gene called FMNL2 links cerebrovascular disease with Alzheimer’s disease and suggests changes in FMNL2 activity caused by cerebrovascular disease that prevent effective clearance 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 have a potential mechanism,” says senior author Richard Mayox, MD, chief of neuroscience at Columbia and New York Presbyterian/Columbia University Irving Medical Center.

“People have been trying to figure this out for two decades, and I think we’ve put our foot in the door now. We feel there must be other genes involved and we just scratched the surface.”

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

One gene, FMNL2, emerged during analysis. But what role it could play was not clear. That’s when Caghan Kizil, PhD, a visiting associate professor at Columbia University, drew on his experience with zebrafish as a model organism for Alzheimer’s disease.

FMNL2 and the blood-brain barrier

“We had this gene, FMNL2, that was located at the interface between Alzheimer’s disease in the brain and cerebrovascular risk factors,” Kizel says. “So we had the idea that FMNL2 might function at the blood-brain barrier, where brain cells meet blood vessels.”

The blood-brain barrier is a semi-permeable and tightly 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, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around blood vessels. This astrocyte sheath needs relaxation to remove toxic amyloid — clumps of proteins that build up in the brain and lead to Alzheimer’s disease.

The zebrafish model confirmed the presence of FMNL2 in the envelope of astrocytes, resulting in a regression of their grip on blood vessels once toxic proteins were injected into the brain, likely to allow clearance. When Kizil and colleagues blocked FMNL2 function, this regression did not occur, preventing the removal of amyloid from the brain. Then the same process was confirmed using genetically modified mice with Alzheimer’s disease.

This shows a heart shaped brain
This discovery could lead to a way to prevent Alzheimer’s disease in people with high blood pressure, diabetes, obesity or heart disease. The image is in the public domain

The same process may also occur in the human brain. Researchers studied human brains after death and found increased expression of FMNL2 in people with Alzheimer’s disease, along with a breach of the blood-brain barrier and a regression of astrocytes.

Based on these findings, the researchers suggest that FMNL2 opens the blood-brain barrier—by controlling astrocytes—and promotes the removal of extracellular pools from the brain. And this cerebrovascular disease, through interaction with FMNL2, reduces the clearance of amyloid in the brain.

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

About this research dementia news

author: press office
source: Columbia University
Contact: Press Office – Columbia University
picture: The image is in the public domain

original search: open access.
FMNL2 regulates glial vascular interactions and is associated with vascular risk factors and cerebrovascular disease in Alzheimer’s disease.Written by Annie J. Lee et al. Acta Neuropathologic


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This indicates a brain

FMNL2 regulates glial vascular interactions and is associated with vascular risk factors and cerebrovascular disease in Alzheimer’s disease.

Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle life and beyond, often with cerebrovascular disease at death.

The interaction between CVRFs and genetic variants may explain the pathogenesis. Genome-wide, the gene was identified by CVRF interaction analyzes for Alzheimer’s disease, in 6568 patients and 8101 controls. FMNL2 (s = 6.6 x 10-7).

significant increase in FMNL2 Expression was observed in the brains of patients with cerebral infarctions and Alzheimer’s disease and was associated with the deposition of amyloid and phosphorous tau. FMNL2 was also prominent in Astroglia in AD among those with cerebrovascular disease.

Increased amyloid toxicity in zebrafish fmnl2a Expression in the stellate astrocyte with detachment of the stellate terminal foot from the vasculature. Knockdown for fmnl2a Preventing glial vascular remodeling, decreasing glial activity and promoting amyloidosis.

APP/PS1dE9 AD mice were also shown increased FMNL2 Expression and reduction of glial vascular connections independently of the glial response. Based on this work, we propose that FMNL2 regulates the pathology-dependent plasticity of the blood-brain barrier by controlling glial-vascular interactions and stimulating the clearance of extracellular aggregates.

Therefore, in cerebrovascular risk factors, cerebrovascular disease promotes which in turn interacts with FMNL2Alteration of the normal stellate vascular mechanisms underlying the removal of amyloid and tau resulting in increased deposition of amyloid and tau in the brain.