According to a recent study conducted by scientists at MIT’s Picower Institute for Learning and Memory, a new drug candidate has shown promising results in reducing inflammation and improving memory in Alzheimer’s disease. While drug developers have made progress in targeting amyloid beta protein, which is associated with the disease, other issues like inflammation still need to be addressed.
The researchers focused on a genetic transcription factor called PU.1, which becomes overactive during Alzheimer’s disease and leads to excessive expression of inflammatory genes in microglial immune cells of the brain. The new drug candidate, known as A11, was found to suppress this activity by recruiting other proteins that repress the inflammatory genes regulated by PU.1. Importantly, A11 primarily targets the brain and does not affect PU.1’s role in producing blood cells.
“Inflammation is a major component of Alzheimer’s disease pathology that has been especially difficult to treat,” says Li Huei Tsai, lead author of the study and Picower Professor of Neuroscience at MIT. The research demonstrated that A11 reduced inflammation in human microglia-like cells and multiple mouse models of Alzheimer’s disease while significantly improving cognition in mice.
The study was published on August 29th in the Journal of Experimental Medicine and was co-authored by Elizabeta Gjoneska of the National Institutes of Health. Previous research led by Gjoneska had identified PU.1 as a regulator of inflammation in mouse models of Alzheimer’s disease.
To validate PU.1 as a therapeutic target, the researchers compared gene expression patterns in postmortem brain samples from Alzheimer’s patients and mouse models with controls without the disease. They observed significant changes in microglial gene expression caused by Alzheimer’s, including increased binding of PU.1 to inflammatory gene targets. Inhibiting PU.1 activity reduced inflammation and neurodegeneration in a mouse model.
To identify potential drugs that could target PU.1, the team screened over 58,000 small molecules from FDA-approved drugs and new chemicals. They discovered that A11 was the most effective in reducing inflammation and Alzheimer’s-related genes regulated by PU.1 in cell cultures.
Further experiments showed that A11 prevented microglia-like cells from overreacting to inflammatory signals. It achieved this by recruiting proteins like MECP2, HDAC1, SIN3A, and DMNT3A, which are known to repress gene expression. Essentially, A11 converted PU.1 from a transcriptional activator to a transcriptional repressor.
In pharmacological tests on mice, A11 demonstrated its ability to cross the blood-brain barrier and effectively reduce inflammation in different mouse models of Alzheimer’s disease. In CK-p25 mice with severe neurodegeneration and Tau P301S transgenic mice with tauopathy, A11 reduced inflammatory responses among microglia and astrocytes while preserving neurons. Additionally, amyloid levels were significantly reduced in 5XFAD mice with amyloid pathology.
The researchers also conducted maze tests to assess memory function in the treated mice. Both CK-p25 and Tau P301S mice performed significantly better than untreated controls in tests of short-term working memory and long-term learning.
While more testing is needed before A11 can be approved as a drug for Alzheimer’s disease treatment, Tsai believes it could complement existing treatments targeting amyloid beta protein. “Since A11 acts through a mechanism other than the existing AD therapies, it could be used alone or in combination with approved therapies to provide better treatment options for neurodegenerative diseases,” she concludes.
The study was funded by the Robert A. and Renee E. Belfer Family Foundation and the National Institutes of Health, with additional support from foundations like JPB Foundation and Halis Family Foundation.
Unusually, these findings offer hope for developing new treatments that address inflammation as a key aspect of Alzheimer’s disease. By targeting PU.1 and reducing inflammation, drugs like A11 could potentially improve cognition and slow down neurodegeneration in patients with Alzheimer’s.
