” Not just do we have a gene, however we have a possible mechanism,” states senior author Richard Mayeux, MD, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical. Thats when Caghan Kizil, PhD, a visiting associate teacher at Columbia, leveraged his proficiency with zebrafish as a design organism for Alzheimers disease.
This astrocyte sheath needs to loosen up for the clearance of hazardous amyloid– the aggregates of proteins that accumulate in the brain and lead to Alzheimers disease.
The zebrafish model confirmed the existence of FMNL2 in the astrocyte sheath, which withdrawed its grip on the blood vessel when toxic proteins were injected into the brain, most likely to allow for clearance. The exact same procedure was then validated using transgenic mice with Alzheimers illness.
The conditions can all affect the brain, damaging blood vessels and causing strokes. However the connection between vascular disease in the brain and Alzheimers has stayed unexplained despite the extreme efforts of scientists.
Now, a study led by scientists at Columbia Universitys Vagelos College of Physicians and Surgeons has actually found a possible system. The study found a gene called FMNL2 links cerebrovascular disease and Alzheimers and recommends modifications in FMNL2 activity brought on by cerebrovascular illness prevent the effective clearance of hazardous proteins from the brain, ultimately causing Alzheimers illness.
The finding might cause a way to avoid Alzheimers in individuals with high blood pressure, heart, diabetes, or obesity illness.
” Not only do we have a gene, but we have a prospective system,” says senior author Richard Mayeux, MD, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical Center. “People have been attempting to figure this out for a couple of years, and I think we have our foot in the door now. We feel there need to be other genes included which weve simply scratched the surface.”
Mayeux and his coworkers discovered FMNL2 in a genome-wide hunt created to discover genes associated with both vascular threat factors and Alzheimers disease. The search involved five groups of patients representing various ethnic groups.
One gene, FMNL2, stood out during the analysis. What function it might possibly play was unclear. Thats when Caghan Kizil, PhD, a going to associate teacher at Columbia, leveraged his proficiency with zebrafish as a model organism for Alzheimers disease.
FMNL2 and the blood-brain barrier
” We had this gene, FMNL2, that was lying at the interface in between Alzheimers disease in the brain and cerebrovascular threat elements,” states Kizil. “So we had a concept that FMNL2 might operate in the blood-brain barrier, where brain cells meet the vasculature.”
The blood-brain barrier is a semi-permeable, highly managed border between capillaries and brain tissue that acts as a defense against disease-causing pathogens and contaminants in the blood. Astrocytes, a specialized kind of brain cell, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around the capillary. This astrocyte sheath needs to loosen up for the clearance of hazardous amyloid– the aggregates of proteins that collect in the brain and lead to Alzheimers illness.
The zebrafish design confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the capillary when harmful proteins were injected into the brain, probably to enable clearance. When Kizil and his associates blocked the function of FMNL2, this retraction did not take place, avoiding clearance of amyloid from the brain. The very same process was then verified using transgenic mice with Alzheimers disease.
The same process may likewise take place in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with Alzheimers disease, along with breach of the blood-brain barrier and retraction of the astrocytes.
Based upon these findings, the scientists propose that FMNL2 opens the blood-brain-barrier– by controlling its astrocytes– and promotes the clearance of extracellular aggregates from the brain. And that cerebrovascular disease, by communicating with FMNL2, decreases the clearance of amyloid in the brain.
The group is presently in the procedure of examining other genes that could be included in the interplay between Alzheimers and cerebrovascular disease, which, along with FMNL2, could supply future techniques for drug development.
Recommendation: “FMNL2 controls gliovascular interactions and is associated with vascular threat elements and cerebrovascular pathology in Alzheimers disease” by Annie J. Lee, Neha S. Raghavan, Prabesh Bhattarai, Tohid Siddiqui, Sanjeev Sariya, Dolly Reyes-Dumeyer, Xena E. Flowers, Sarah A. L. Cardoso, Philip L. De Jager, David A. Bennett, Julie A. Schneider, Vilas Menon, Yanling Wang, Rafael A. Lantigua, Martin Medrano, Diones Rivera, Ivonne Z. Jiménez-Velázquez, Walter A. Kukull, Adam M. Brickman, Jennifer J. Manly, Giuseppe Tosto, Caghan Kizil, Badri N. Vardarajan and Richard Mayeux, 24 May 2022, Acta Neuropathologica.DOI: 10.1007/ s00401-022-02431-6.
Richard Mayeux, MD, is the Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology, director of the Gertrude H. Sergievsky Center, and co-director of the Taub Institute for Research on Alzheimers Disease and the Aging Brain at Columbia University.
The research was supported by the National Institutes of Health (grants RF1AG054023, R01AG067501, RF1AG066107, R01AG072474, P30AG10161, R01AG15819, R01AG17917, R01AG036836, u01ag61356, and u01ag046152); a Taub Institute Schaefer Research Scholar Award; the German Center for Neurodegenerative Diseases; and TAME-AD (The Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimers Disease and Related Disorders of the Nervous System).
All authors: Annie J. Lee (Columbia), Neha S. Raghavan (Columbia), Prabesh Bhattarai (Columbia and German Center for Neurodegenerative Diseases), Tohid Siddiqui (German Center for Neurodegenerative Diseases), Sanjeev Sariya (Columbia), Dolly Reyes-Dumeyer (Columbia), Xena E. Flowers (Columbia), Sarah A.L. Cardoso (Columbia), Philip L. De Jager (Columbia), David A. Bennett (Rush University Medical Center), Julie A. Schneider (Rush University Medical Center), Vilas Menon (Columbia), Yanling Wang (Rush University Medical Center), Rafael A. Lantigua (Columbia), Martin Medrano (Pontificia Universidad Catolica Madre y Maestra, Dominican Republic), Diones Rivera (Universidad Pedro Henriquez Urena, Dominican Republic), Ivonne Z. Jiménez-Velázquez (University of Puerto Rico School of Medicine), Walter A. Kukull (University of Washington), Adam M. Brickman (Columbia), Jennifer J. Manly (Columbia), Giuseppe Tosto (Columbia), Caghan Kizil (Columbia and German Center for Neurodegenerative Diseases), Badri N. Vardarajan (Columbia), and Richard Mayeux (Columbia).
Scientists might have uncovered a possible mechanism for why individuals with high blood pressure, diabetes, high cholesterol, or weight problems have actually an increased chance of developing Alzheimers illness.
Alzheimers illness is the leading cause of dementia in older adults and the 7th most common cause of death in the United States according to the National Institute on Aging. It is a debilitating progressive health problem that starts with moderate memory loss and gradually destroys cognitive function and memory.
As the name indicates, vascular illness are conditions that impact your vascular system, which is your bodys network of blood vessels.
For more than 20 years, scientists have known that people with high blood pressure, diabetes, high cholesterol, or weight problems have a higher likelihood of developing Alzheimers disease.