Mount Sinai Researchers Identify Protein that Protects Against Alzheimer’s Disease
Detailed predictive analyses and functional studies show that the VGF protein protects against onset and progression of Alzheimer’s disease, paving the way for future drug discovery efforts
A protein known as VGF plays a key role in protecting the brain against Alzheimer’s disease, according to results from a large study conducted by scientists from the Icahn School of Medicine at Mount Sinai, Emory University, and collaborating institutions. This discovery, made possible through big data modeling and multiscale analyses, provides a new target for researchers seeking drugs to treat Alzheimer’s. The paper was published on Friday, August 7, in Nature Communications.
Despite intensive research, the molecular underpinnings of Alzheimer’s disease have not yet been fully characterized. Genome-wide association studies have implicated more than two dozen genetic regions associated with disease risk, but this information has proven difficult to translate into clinical use.
In this study, scientists built predictive network models of late-onset Alzheimer’s disease by mining DNA, RNA, protein, and clinical data. These models allowed them to identify key regulators of the disease and spotlighted VGF, the only key driver of a suppressed response across all datasets. VGF is a neuronal protein that regulates memory; levels of it are reduced in the brains and cerebrospinal fluid of patients with Alzheimer’s disease.
“Our results support previous studies in demonstrating that the biology of Alzheimer’s disease is highly complex, and that there is no single genetic cause of the disease,” said Noam Beckmann, PhD, a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai and a lead author of the paper. “However, our sophisticated model and follow-up validation studies offer convincing evidence that the protein VGF, previously associated with fear and spatial memories in mice, plays an important role in protecting the brain against the onset and progression of Alzheimer’s disease.”
While lower levels of VGF had been noted in previous Alzheimer’s disease studies, this is the first time that reduced levels of the protein have been shown to have a causal role in the disease. Scientists replicated the VGF findings in other datasets, and then used multiple mouse models to study overexpression of VGF. By dialing up levels of the gene or protein in mice, scientists were able to significantly reduce pathogenesis and progression of Alzheimer’s disease, with clear molecular and behavioral effects.
“Our combined big data analysis of gene expression in patients with Alzheimer’s disease and validation studies carried out in mouse models provide novel insights into disease mechanisms,” said Stephen R. J. Salton, MD, PhD, Professor of Neuroscience, and Geriatrics, at the Icahn School of Medicine at Mount Sinai. “These studies have identified molecular networks and new gene products including VGF that impact Alzheimer’s disease, for future pharmacotherapeutic manipulation, which we anticipate will lead to a reduction in the pathogenesis and progression of this and potentially other neurodegenerative diseases.”
This work was supported by the National Institutes of Health, the National Institute on Aging, the BrightFocus Foundation, the Alzheimer’s Drug Discovery Foundation, the Cure Alzheimer’s Fund, the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium, the Guangdong Science and Technology Department, and the National Natural Science Foundation of China.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.