Molecular docking predicts a CLEAR DNA-binding region in ApoE4. a The DNA binding region of ApoE4, as defined by molecular modeling. b The predicted CLEAR-DNA binding pose is shown for ApoE4. c Amino acid residues in the region of ApoE4 that interacts with CLEAR DNA are highlighted in yellow. d The root mean square deviation (RMSD) of the molecular structure of ApoE4 was calculated from 300 ns molecular dynamics simulations, indicating relative conformational stability. e Number of internal hydrogen bonds (H-bonds) in the ApoE4 protein calculated from 300 ns molecular dynamics simulation trajectories. Credit: Communication biology (2024). DOI: 10.1038/s42003-024-05767-9
A potential new drug to prevent Alzheimer’s disease in people carrying the so-called Alzheimer’s gene has been discovered by a research team at the University of Arkansas for Medical Sciences (UAMS) led by Sue Griffin, Ph. .D.
The results were published on January 8 in Communication biology and include discoveries of a drug target and drug candidate made by Meenakshisundaram Balasubramaniam, Ph.D., the paper’s first author.
It is estimated that 50 to 65% of people with Alzheimer’s disease have inherited the Alzheimer’s disease gene, apolipoprotein E4 (APOEε4), from one or both parents. About 25% of people have one copy of APOEε4 and are three times more likely to develop the disease. Those who have two copies (one from each parent) represent 2 to 3% of the population and are 12 to 15 times more likely to develop Alzheimer’s disease.
Griffin said her team appears to be the first to make new drug-related discoveries, just as they were the first in 2018 to show how APOEε4 stopped brain cells from getting rid of their waste, known as lysosomal autophagy.
Such disruption of autophagy in those who inherit APOEε4 is responsible for the formation of plaques and tangles in the brain, characteristic of Alzheimer’s disease. This discovery was published in Alzheimer’s and dementia.
“Our series of discoveries related to APOEε4 and its detrimental role in the pathogenesis of Alzheimer’s disease are among the most significant in my 50 years as a research scientist,” said Griffin, a pioneer in the study of neuroinflammation. and co-founder of Journal of Neuroinflammation, based at the UAMS Donald W. Reynolds Institute on Aging. “No other research team has found a potential drug specifically to block the harmful effects of hereditary APOEε4.”
Griffin is the Alexa and William T. Dillard Chair in Geriatric Research and a distinguished professor in the College of Medicine and director of research at the Institute on Aging. She is also a professor in the College’s departments of neurobiology and developmental sciences, internal medicine and psychiatry. Notably, she is a recipient of the Alzheimer’s Association’s Lifetime Achievement Award and an inductee into the Arkansas Women’s Hall of Fame.
Most Alzheimer’s research nationwide has focused on treatments that can clear the brain plaques and tangles associated with the disease, but that approach has yielded unimpressive results. Griffin notes that people with mild symptoms of Alzheimer’s disease have already lost about half or more of the neurons responsible for memory and reasoning, leading her to focus on prevention.
Griffin’s team will conduct larger-scale preclinical research on the drug candidate CBA2, as well as test other potential drug candidates.
“We hope that people who have one or two copies of APOEε4 will one day take this drug regularly throughout their lives and significantly reduce their risk of developing Alzheimer’s disease,” Griffin said.
Balasubramaniam said UAMS constructed the first known complete structure of the APOEε4 protein in 2017, which it created using bioinformatics and computer modeling techniques. This fundamental work led to the discovery of the druggable site on the APOEε4 protein, ApoE4. (APOEε4 refers to the gene, and ApoE4, without the epsilon symbol and without italics, is the protein.)
Balasubramaniam’s unique skills and curiosity, Griffin said, were the catalyst for these discoveries.
“I don’t know of anyone else in the world other than Dr. Balasubramaniam who can do the work described in this article,” Griffin said of the Inglewood assistant professor and researcher in the Department of Geriatrics.
While most institutions still screen drug compounds manually, which can take years, Balasubramaniam oversees a computational biology suite with high-performance GPU servers that he used to screen about 800,000 compounds in two days.
His computer-simulated findings on ApoE4-targeted drug actions have been validated in various in vitro and in vivo model systems.
Collaborating investigators include: Srinivas Ayyadevara, Ph.D., associate professor, Department of Geriatrics; Steve W. Barger, Ph.D., professor, departments of geriatrics, neurobiology and developmental sciences, and internal medicine; Peter Crooks, Ph.D., D.Sc., Professor, Department of Pharmaceutical Sciences, College of Pharmacy, Simmons Chair in Cancer Research; Robert JS Reis, Ph.D., professor in the departments of geriatrics, biochemistry and molecular biology, and pharmacology and toxicology.
A provisional patent has been issued for the CBA2 drug candidate and full patent approval is pending.
More information:
Meenakshisundaram Balasubramaniam et al, Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer’s disease by targeted small molecules, Communication biology (2024). DOI: 10.1038/s42003-024-05767-9
Provided by University of Arkansas for Medical Sciences
Quote: Research team discovers potential drug for Alzheimer’s disease (February 6, 2024) retrieved February 6, 2024 from
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