People with obesity, hypertension, and diabetes have a greater risk of Alzheimer’s disease. Despite these associations, scientists remain stumped as to why these two different conditions — Alzheimer’s and vascular disease — are connected. However, a new study suggests the link may come from mutations in the FMNL2 gene.
Disruption of the FMNL2 gene from cerebrovascular disease thwarts the body’s efforts to remove toxic proteins from the brain. An inefficient clean-up allows toxic waste to pile up on the brain, eventually causing Alzheimer’s disease. Understanding the mechanism between the two conditions could help scientists develop treatments for people with hypertension or obesity to prevent Alzheimer’s from expanding.
“Not only do we have a gene, but we have a potential mechanism,” says senior author Dr. Richard Mayeux, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical Center, in a statement. “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 feel there must be other genes involved and that we’ve just scratched the surface.”
Researchers uncovered the FMNL2 gene after comparing different genes from five groups of patients with different ethnic groups. While the role of the FMNL2 gene remained unclear, one hypothesis was that FMNL2 may have something to do with the blood-brain barrier.
The blood-brain barrier is a semi-permeable barricade that selectively allows certain substances to enter the brain while keeping toxins and disease-causing pathogens away. Astrocytes are brain immune cells in charge of maintaining the blood-brain barrier structure.
Using a zebrafish model, the researchers found the astrocytes loosen up their hold on the blood-brain barrier when expelling toxic amyloid proteins from the brain. The FMNL2 gene is in astrocytes and is likely expressed when allowing the brain to clear out toxins. Blocking the FMNL2 gene prevented astrocytes from opening up the barrier, allowing the abnormal amyloid protein to continue clumping in the brain. A separate mice model of Alzheimer’s disease confirmed the results. Additionally, researchers found the FMNL2 gene in people who died from Alzheimer’s disease was altered.
The researchers propose that in a healthy brain, the FMNL2 gene allows the blood-brain barrier to open up and dump out toxic waste from the brain. However, vascular diseases affect FMNL2 and prevent the brain from clearing amyloid protein. The team is now working on identifying other genes besides FMNL2 that could be involved in the two diseases. Doing so could lead to more avenues for drug development.
The study is published in the journal Acta Neuropathologica.
