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Summary: The FMNL2 gene links cerebrovascular disease and Alzheimer’s disease, a new study reports. Activity changes in FMNL2 caused by cerebrovascular disease prevent efficient clearing of toxic proteins in the brain, leading to the development of Alzheimer’s disease.
Source: University of Columbia
For more than 20 years, scientists have known that people with high blood pressure, diabetes, high cholesterol or obesity have a higher risk of developing Alzheimer’s disease.
The disorders can all affect the brain, damage blood vessels and lead to strokes. But the connection between vascular diseases in the brain and Alzheimer’s disease remained unclear, despite intensive efforts by the researchers.
A study now published in Acta Neuropathologica and uncovered a possible mechanism, led by researchers from Columbia University’s Vagelos College of Physicians and Surgeons.
The study found that a gene called FMNL2 links cerebrovascular disease and Alzheimer’s and suggests that cerebrovascular disease-induced changes in FMNL2 activity prevent the efficient removal of toxic proteins from the brain, eventually leading to Alzheimer’s disease.
The discovery could lead to a way to prevent Alzheimer’s 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 senior 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 couple 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 uncovering genes linked to both vascular risk factors and Alzheimer’s disease. The search included five groups of patients representing different ethnic groups.
One gene, FMNL2, stood out during the analysis. But what role it could possibly play was unclear. At that point, Caghan Kizil, Ph.D., an associate visiting professor at Columbia, was using his expertise in zebrafish 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 had 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 as a defense against disease-causing pathogens and toxins in the blood.
Astrocytes, a specialized type of brain cell, build and maintain the structure of the blood-brain barrier by forming a protective covering around blood vessels. This astrocyte covering must break down to clear 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 then confirmed using transgenic mice with Alzheimer’s disease.
The same process can also take place in the human brain. The researchers examined postmortem human brains and found increased expression of FMNL2 in people with Alzheimer’s disease, along with blood-brain barrier breakthrough and astrocyte retraction.
Based on these results, the researchers propose that FMNL2 opens the blood-brain barrier – by controlling 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 that may be involved in the interaction between Alzheimer’s and cerebrovascular diseases, which together with FMNL2 could provide future approaches for drug development.
About this news from dementia research
Author: press office
Source: University of Columbia
Contact: Press Office – Columbia University
Picture: The image is in the public domain
Original research: Open access.
“FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease” by Annie J. Lee et al. Acta Neuropathologica
abstract
See also
FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease
Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) in middle age and later, and is often accompanied by cerebrovascular pathology at death.
An interaction between CVRFs and genetic variants could explain the pathogenesis. Genome-wide gene-by-CRF interaction analyzes for AD identified in 6568 patients and 8101 controls FMNL2 (p = 6.6 × 10–7).
A significant increase in FMNL2 Expression was observed in the brains of patients with cerebral infarction and AD pathology and was associated with the deposition of amyloid and phosphorylated tau. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology.
Increased amyloid toxicity in zebrafish fmnl2a Expression in astroglia with detachment of astroglial end-feet from blood vessels. precipitation from fmnl2a prevents gliovascular remodeling, reduced microglial activity and increased amyloidosis.
APP/PS1dE9 AD mice also showed increased values fmnl2 expression and reduced gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent blood-brain barrier plasticity by controlling gliovascular interactions and stimulating clearance of extracellular aggregates.
Thus, in AD, cerebrovascular risk factors promote, and in turn interact with, cerebrovascular pathology FMNL2Alteration of the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau, increasing their deposition in the brain.
