Approximately 1 in 9 people aged 65 and older have Alzheimer’s disease, the most common type of dementia. By 2050, an estimated 12.7 million Americans will be living with the degenerative disease and the long-term total health care costs are predicted to hit nearly $1 trillion. However, there are new encouraging findings from Massachusetts Institute of Technology researchers who point to a molecule that can potentially preserve cognitive function while reining in Alzheimer’s-related brain inflammation.
The National Institutes of Health and the Robert A. and Renee E. Belfer Family Foundation funded the Alzheimer’s study, which was published in the Journal of Experimental Medicine on August 29. In it, scientists reveal a newly discovered molecule which has a groundbreaking effect on PU.1, a DNA-binding nuclear protein and a central antagonist of inflammation in Alzheimer’s patients.
“Inflammation is a major component of Alzheimer’s disease pathology that has been especially hard to treat,” says study senior author Li-Huei Tsai, Picower Professor of Neuroscience at MIT and director of The Picower Institute and MIT’s Aging Brain Initiative. “This preclinical study demonstrates that A11 reduces inflammation in human microglia-like cells, as well as in multiple mouse models of Alzheimer’s disease, and significantly improves cognition in the mice. We believe A11 therefore merits further development and testing.”
William Ralvenius, a Picower Institute for Learning and Memory research scientist, led the study alongside co-authors Tsai and NIH’s Elizabeta Gjoneska.
The researchers studied more than 58,000 small molecules from Food and Drug Administration-approved novel chemicals and drugs. They focused on determining if any could safely reduce inflammation and the Alzheimer’s-related genes controlled by PU.1 in cell cultures. After multiple rounds of meticulous screening, the scientists identified six chemicals with capabilities and recognized that A11 was the most promising.
The new study’s findings are encouraging, since the A11 drug compound targets inflammation caused by PU.1 in Alzheimer’s disease, yet it doesn’t impede the protein’s capacity to make necessary blood cells.
According to the study, the A11 molecule turns PU.1 “from a transcriptional activator to a transcriptional repressor.” This process results in a controlled state of microglial inflammation. Microglial cells manage immune surveillance within the central nervous system. These cells respond to noxious stimuli by discharging inflammatory mediators and producing an adequate inflammatory response.
Mice Models a Key Research Component
Mice models have been vitally important to making progress in the analysis of the disease and potential treatments. The newest study looked at how the A11 compound worked on PU.1 in Alzheimer’s mouse models and human microglia-like cells harvested from patient stem cells.
Researchers studied the A11 compound’s effects in multiple mouse strains. Each of the three mice had different features of Alzheimer’s. The MIT scientists found that the A11 compound decreased inflammation — and in the mouse models, it improved cognitive function.
According to the study, the researchers found that in mice, the A11 can simply cross the blood-brain barrier, which is essential for targeted treatments, and continue to exist in brain cells for a more extended period of time than anywhere else in the mice models. By captivating other proteins that reduce inflammatory genesis, the medicine can also subdue undesirable PU.1 activity.
The researchers built mazes to study mice with tauopathy — neurodegenerative disorders distinguished by the presence of abnormal tau protein in the brain — and neurodegeneration, the progressive loss of function or structure of neurons, which results in cellular atrophy.
These mazes were designed to gauge the rodents’ long-term learning and short-term working memory. They found that all mice treated with the A11 compound were significantly better at performing the tasks than the untreated controls. For example, in a water maze, the mice given the compound remembered where a platform was located and could rest faster than those not treated with A11.
Since the molecule has great therapeutic potential and can potentially complement existing and emerging Alzheimer’s treatments, Tsai stated, “We believe A11, therefore, merits further development and testing.”
The Belfer Family: Longtime Supporters of Finding Treatments for Aging-Associated Diseases
The Robert A. and Renee E. Belfer Family Foundation was integral in the creation of the Neurodegeneration Consortium. It was established in 2012 to focus on finding treatments for neurodegenerative diseases. “An aging population challenges us with runaway medical costs,” stated Robert Belfer. “To enhance the quality of life in later years, as well as reduce costs, we need a national effort.”
Belfer said that the consortium’s purpose is “to translate research findings into effective targeted drugs and diagnostics for patients while addressing quality-of-life issues and the financial challenges of treating and living with Alzheimer’s and other aging diseases.”
Eight years ago, the Belfer family and the NIH’s funded study first discovered the role of PU.1 in Alzheimer’s. Subsequent investigations and drug screenings have led to the detection of a potential new Alzheimer’s drug that curbs the negative inflammatory response of the brain’s microglia. The drug demonstrated its potential in preclinical tests to improve cognition, preserve neurons, and reduce disease pathology.
In addition to the National Institutes of Health and Robert A. and Renee E. Belfer Family Foundation, assistance was provided by The Halis Family Foundation, Lester A. Gimpelson, Jay L. and Caroll Miller, the JPB Foundation and the Picower Institute.
John Davis is a seasoned health journalist with expertise in public health and medical research. Holding a degree in health sciences, John excels in making complex health topics understandable and engaging for his readers. His articles, featured in top health publications, cover everything from cutting-edge treatments to public health policies. Outside of journalism, John is an advocate for health education and frequently speaks at community events.
