Scientists at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology (MIT) have discovered a potential new Alzheimer’s disease (AD) drug, A11, could reduce inflammation and improve memory.
Funded by the Robert A and Renee E Belfer Family Foundation and the National Institutes of Health, the scientists found that A11 repressed harmful inflammatory responses of the brain’s immune cells, reducing disease pathology, preserving neurons and improving cognition in preclinical testing.
After comparing the gene expression of immune cells in post-mortem brain samples from AD patients and AD mouse models, researchers found that Alzheimer’s effected major changes in microglial gene expression and that PU.1 binding to inflammatory gene targets was a significant part of that change.
The target of the A11 molecule is a genetic transcription factor known as PU.1, which takes control of inflammatory gene expression in the brain’s microglia immune cells and ensures the production of a wide variety of blood cells.
Researchers found that A11 suppressed PU.1 activity by recruiting other proteins that repressed the inflammatory genes that PU.1 works to express without disrupting its other role.
After the scientists screened over 58,000 small molecules from US Food and Drug Administration-approved drugs and novel chemical libraries, they narrowed the field down to six chemicals, of which A11 was the most potent.
They found that A11-treated cells exposed to inflammatory triggers behaved like unperturbed microglia, suggesting that A11 helps to prevent microglia from overreacting to inflammatory cues.
PU.1 activity was also reduced in mouse models of AD, resulting in reduced inflammation and the death of neurons (neurogeneration).
Pharmacological mouse tests indicated that A11 was cleared from tissues and capable of reaching brain cells after the chemical successfully crossed the blood-brain barrier and remained in brain cells much longer than anywhere else in healthy mice.
Based on the study results, Li-Huei Tsai, senior author of the study, professor of neuroscience at Picower and director of Picower and MITs Ageing Brain Initiative, said: “We believe A11 therefore merits further development and testing.”
“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,” said the study authors.
According to Tsai, further testing is suggested before A11 could become an approved medicine; however, it could complement new treatments that target amyloid.