MIT Scientists Say Novel Molecule in Alzheimer's Study Funded by the Belfer Family and NIH Warrants Further Testing

Researchers say there's been a positive breakthrough in Alzheimer's research. On August 29th, 2023, the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology published encouraging findings in the Journal of Experimental Medicine. Li-Huei Tsai, Picower professor of neuroscience at MIT and director of the Picower Institute and MIT's Aging Brain Initiative, co-authored the study with the National Institutes of Health's Elizabeta Gjoneska. The NIH and the Robert A. and Renee E. Belfer Family Foundation funded the research.

The Belfer family has been supporting these efforts for over a decade. The Foundation's generosity helped create the Neurodegeneration Consortium in 2012 to concentrate on finding treatments for neurodegenerative diseases and Alzheimer's.

Said Robert Belfer: "The aim 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."

Specifically Targeting Inflammation

Picower Institute research scientist William Ralvenius led the research described in the new study in which the MIT scientists discovered the benefits of a drug compound named A11 on PU.1, a DNA-binding nuclear protein. This study's findings are groundbreaking because the A11 drug compound specifically targets the inflammation caused by PU.1 in Alzheimer's disease without hindering the protein's ability to produce vital blood cells.

By using the newly discovered A11 compound on PU.1 in Alzheimer's mouse models and human microglia-like cells cultivated from patient stem cells, researchers discovered it reduced inflammation. In the mouse models, it also improved cognitive function.

The authors wrote, "A11 represents a first-in-class molecule that converts PU.1 from a transcriptional activator to a transcriptional repressor, resulting in a controlled state of microglial inflammation."

A11 is a new and unique drug compound created to improve Alzheimer's disease, specifically targeting overactive inflammation, and could have the potential to be combined with other existing therapies, like the approved anti-amyloid antibodies, for additional benefit. Earlier research showed that PU.1 becomes an overactive administrator of inflammatory gene expression in the brain's microglia immune cells.

A11 is a first-in-class compound that converts the overactive PU.1 to specific repressed activity. This is especially important because the medication appears to be able to control the problem without causing more damage since PU.1 is needed for other body functions, and genetically demolishing it isn't viable.

New research shows that A11 easily crossed the blood-brain barrier in mice and remained in brain cells much longer than anywhere else. Researchers found that the compound also has the ability to suppress the unwanted PU.1 activity by engaging other proteins that repress the inflammatory genes.

The research team screened over 58,000 small molecules from Food and Drug Administration-approved drugs and novel chemicals to see if any could safely and significantly reduce inflammation and Alzheimer-related genes controlled by PU.1 in cell cultures. After multiple rounds of rigorous screening, the researchers pinpointed six chemicals, with A11 being the most potent of the lot.

Tsai stated, "Inflammation is a major component of Alzheimer's disease pathology that has been especially hard to treat. 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."

The Role of Mouse Models in Drug Discovery

The National Institutes of Health and Belfer family-funded study first led to the discovery of the role of PU.1 in Alzheimer's in 2015. Since then, the follow-up work done to screen drugs that could help and test its top compounds in animal models and human cells has resulted in the discovery of a potential new Alzheimer's drug that quells the harmful inflammatory response of the brain's microglia. As a result, it reduces disease pathology, improves cognition, and preserves neurons in preclinical tests. Mice models have been essential to better understanding the disease and potential treatments.

The MIT researchers examined the A11 compound's effects in three mouse strains, each with different aspects of the disease.

The mice with severe neurodegeneration that were given A11 displayed less inflammatory response in astrocyte and microglia cells. Those mice also lost fewer neurons than the untreated mice. The ones with amyloid pathology, or the accumulation of amyloid beta protein in the brain, leading to neuronal toxicity in the central nervous system, experienced a significant reduction in amyloid.

The rodents with tauopathy—neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain—had a similar response. They displaced a noticeable reduction of phosphorylated tau protein in the section of the brain that is a crucial area for memory.

The mice samples with neurodegeneration and tauopathy were studied in mazes created to assess their short-term working memory and longer-term learning. All of the A11-treated mice executed the tasks remarkably better than the untreated controls. When the mice were introduced to a water maze, mice treated with A11 learned the location of a platform where they could rest much more quickly than mice not treated with the compound.

Money Matters

More than 6 million people of all ages in the United States are living with Alzheimer's disease. By 2050, that number is expected to reach approximately 12.7 million Americans. In fact, in 2023, Alzheimer's and dementia will cost the United States $345 billion, which excludes the value of unpaid caregiving. By 2050, the total cost of health care, hospice care, or long-term care for those living with dementia is estimated to reach nearly $1 trillion.

Considering the total lifetime cost of care for an individual living with Alzheimer's or dementia is approximately $392,874, the findings from the Robert A. and Renee E. Belfer Family Foundation and the National Institutes of Health-funded study are a welcome step in the right direction.

"Neurodegenerative diseases including Alzheimer's are, like cancer, diseases of aging," said Robert Belfer. "An aging population challenges us with runaway medical costs. To enhance the quality of life in later years, as well as reduce costs, we need a national effort."

Much more testing needs to be conducted before A11 can become an approved medication, but Tsai is confident that it has the potential to complement new treatments that target amyloid.

The study's authors wrote, "Given that A11 acts via a distinct mechanism from existing [Alzheimer's disease] therapeutics, A11 could be used alone or in combination with approved therapeutics to provide improved treatment options for neurodegenerative disease."