There has been progress in developing treatments for Alzheimer’s disease that reduce amyloid-beta protein. However, there is a need for treatments that also reduce inflammation as it has been hard to treat. Now, a new study by scientists at the Picower Institute for Learning and Memory at MIT demonstrates a drug candidate that reduces inflammation and improves memory in human cell cultures and Alzheimer’s mouse models.

The findings are published in the Journal of Experimental Medicine in an article titled, “A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.”

“Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer’s disease (AD),” the scientists wrote. “SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding.”

Prior research has shown that PU.1 becomes a director of inflammatory gene expression in the brain’s microglia immune cells. The new research shows that A11 suppresses PU.1 activity by recruiting other proteins that repress the inflammatory genes PU.1 works to express. However because A11 concentrates mostly in the brain and does not reduce PU.1 levels, it does not appear to disrupt PU.1’s other job, which is to ensure the production of a wide variety of blood cells.

The team screened more than 58,000 small molecules from libraries of FDA-approved drugs and novel chemicals to see if any could safely and significantly reduce key inflammation and AD-related genes regulated by PU.1 in cell cultures. After several rounds of increasingly stringent screening, they narrowed the field down to six chemicals. A11 was by far the most potent among them.

“Inflammation is a major component of Alzheimer’s disease pathology that has been especially hard to treat,” said study senior author Li-Huei Tsai, PhD, 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.”

The scientists compared gene expression in immune cells of postmortem brain samples from Alzheimer’s patients and mouse models and matching non-Alzheimer’s controls. The comparisons showed that Alzheimer’s affects major changes in microglial gene expression and that an increase in PU.1 binding to inflammatory gene targets was a significant component of that change.

They tested the effects of A11 doses on the function of human microglia-like cells cultured from patient stem cells. When they exposed the microglia-like cells to immune molecules that typically trigger inflammation, cells dosed with A11 exhibited reduced expression and secretion of inflammatory cytokines and less of the cell body shape changes associated with microglia inflammatory responses.

The cells also showed less accumulation of lipid molecules, another sign of inflammatory activation. Looking at gene expression patterns, the scientists observed that A11-treated cells exposed to inflammatory triggers behaved much like unperturbed microglia, suggesting that A11 helps prevent microglia from overreacting to inflammatory cues.

“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,” the authors wrote.

Pharmacological tests indicated that A11 is readily cleared from tissues and is capable of reaching brain cells. The scientists also observed the chemical successfully crossed the blood-brain barrier and remained in brain cells much longer in healthy mice.

More testing needs to be done before A11 could become an approved medicine, Tsai said, but she noted that it could complement the new treatments that target amyloid.

“Given that A11 acts via a distinct mechanism from existing AD therapeutics, A11 could be used alone or in combination with approved therapeutics to provide improved treatment options for neurodegenerative diseases,” the scientists concluded.

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