Newswise — New York, NY — August 18, 2020 — 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
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality care—from prevention to treatment of the most serious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty and our physicians in the top 1% of all physicians nationally by U.S. News & World Report.
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