Summary: Researchers identify the FMNL2 gene as a link between cerebrovascular disease and Alzheimer’s disease. Altered FMNL2 activity associated with vascular damage appears to impede the brain’s ability to clear toxic protein aggregates, potentially driving Alzheimer’s pathology.
Source: Columbia University
For more than two decades, clinical studies have shown that people with hypertension, diabetes, high cholesterol, or obesity face a higher risk of developing Alzheimer’s disease.
Those cardiovascular and metabolic conditions can damage the brain’s blood vessels and increase the chance of strokes, but exactly how cerebrovascular disease contributes to Alzheimer’s has been unclear. A new study led by Columbia University Vagelos College of Physicians and Surgeons offers a plausible biological mechanism linking vascular risk to Alzheimer’s pathology.
Published in Acta Neuropathologica, the study identifies FMNL2 as a candidate gene that connects cerebrovascular disease and Alzheimer’s disease. The researchers propose that changes in FMNL2 activity triggered by vascular injury alter the blood-brain barrier and impair removal of toxic protein aggregates—such as amyloid—thereby promoting Alzheimer’s development.
“Not only do we have a gene, but we have a potential mechanism,” says senior 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 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.”
The team discovered FMNL2 through a genome-wide search for genes whose effects interact with vascular risk factors and are associated with Alzheimer’s. Their analysis included five patient groups from different ethnic backgrounds. FMNL2 emerged as a notable hit, prompting follow-up experiments to determine its role.
Caghan Kizil, PhD, a visiting associate professor at Columbia with experience using zebrafish to model neurodegenerative processes, investigated how FMNL2 might function at the interface of brain cells and blood vessels.
FMNL2, astrocytes and the blood-brain barrier
The blood-brain barrier is a tightly regulated interface that separates the brain’s tissue from circulating blood, protecting neural tissue from pathogens and toxins. Astrocytes—specialized glial cells—form a sheath around blood vessels and help regulate this barrier. To clear extracellular toxic proteins like amyloid, the astrocyte sheath must undergo controlled remodeling to allow removal of these aggregates.
Using zebrafish models, the researchers showed that FMNL2 is present in astrocytic structures that contact blood vessels. When toxic protein aggregates were introduced into the zebrafish brain, FMNL2-dependent retraction of astrocyte end feet from the vessel wall occurred, a change that appears to allow clearance of the aggregates. Blocking FMNL2 function prevented this remodeling, impaired microglial responses, and reduced amyloid clearance. Similar changes were observed in transgenic mouse models of Alzheimer’s.
Postmortem analysis of human brains supported the animal findings. People with Alzheimer’s disease and cerebrovascular pathology showed increased FMNL2 expression, evidence of blood-brain barrier disruption, and altered astrocyte positioning. Taken together, the data support a model in which FMNL2 modulates gliovascular interactions: when FMNL2 activity is intact, astrocytic remodeling facilitates clearance of extracellular aggregates; when vascular disease alters FMNL2 function, clearance is impaired and toxic proteins accumulate.
This mechanism helps explain how midlife vascular risk factors can translate into increased Alzheimer’s pathology later in life. Cerebrovascular disease may promote vascular damage that, via interactions with FMNL2, disrupts astroglial-vascular mechanisms necessary for clearing amyloid and tau, thereby increasing their deposition in the brain.
The authors emphasize that FMNL2 is likely one of multiple genes and pathways linking cerebrovascular disease and neurodegeneration. The research team is now searching for additional genetic contributors to the cerebrovascular–Alzheimer’s connection. Identifying other genes and understanding their roles could open new avenues for therapeutic development aimed at preserving blood-brain barrier function and enhancing clearance of toxic proteins to prevent or slow Alzheimer’s progression.
About this dementia research news
Author: Press Office
Source: Columbia University
Contact: Press Office – Columbia University
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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
FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease
Alzheimer’s disease (AD) is frequently accompanied by cardiovascular and cerebrovascular risk factors and shows cerebrovascular pathology at death in many cases. An interaction between these risk factors and genetic variants may help explain disease pathogenesis. Genome-wide analyses of gene-by–vascular risk factor interactions in a cohort of 6,568 patients and 8,101 controls identified FMNL2 (p = 6.6 × 10−7) as associated with AD when considering vascular risk context.
FMNL2 expression was increased in brains with infarcts and AD pathology and correlated with amyloid and phosphorylated tau deposition. FMNL2 was particularly prominent in astroglia among individuals with cerebrovascular pathology. In zebrafish, amyloid exposure increased fmnl2a expression in astroglia and caused detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented this gliovascular remodeling, reduced microglial activity, and worsened amyloidosis. APP/PS1dE9 mouse models also showed increased Fmnl2 expression and reduced gliovascular contacts independent of gliosis.
The authors propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain barrier by controlling gliovascular interactions and promoting clearance of extracellular aggregates. Thus, cerebrovascular risk factors may drive cerebrovascular pathology that interacts with FMNL2 to disrupt astroglial–vascular clearance mechanisms, increasing amyloid and tau accumulation in the brain.