Alzheimer's brain inflammation: New molecule targets key culprit

Evan Walker
Evan Walker TheMediTary.Com |
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A study in mice shows that a new molecule may help treat Alzheimer’s symptoms by reducing brain inflammation. Image credit: George Jason/Getty Images.
  • Scientists at The Picower Institute for Learning and Memory at MIT may have taken a significant step toward addressing inflammation, a particularly challenging aspect of Alzheimer’s disease.
  • A new study reveals that a molecule called A11 can dampen inflammation and enhance cognitive function in human-like cells and Alzheimer’s mouse models.
  • By targeting a gene transcription factor named PU.1 — known to become overactive in Alzheimer’s disease — A11 is able to inhibit the gene’s ability to promote inflammation in the brain’s microglial immune cells without interfering with its other crucial roles in the body.

This preliminary study, published in the Journal of Experimental Medicine, reveals that A11 effectively reduces inflammation in cells similar to human microglia and also in several Alzheimer’s mouse models, while notably enhancing cognitive function in the mice.

While there has been some advancement in treating Alzheimer’s disease through medications that lower amyloid-beta protein levels, other issues like inflammation remain unaddressed.

The new molecule, known as “A11,” aims to inhibit a genetic transcription factor named PU.1.

Previous studies have indicated that in the context of Alzheimer’s disease, PU.1 becomes excessively active in promoting inflammation through gene expression in the brain’s microglia immune cells.

According to the new findings, A11 curtails this problematic activity of PU.1 by enlisting other proteins to suppress the inflammatory genes that PU.1 is involved in activating.

The research group had previously conducted studies that identified PU.1 as a key factor in regulating excessive inflammation in microglia in Alzheimer’s mouse models.

This new research commenced with experiments designed to further confirm the therapeutic potential of targeting PU.1. To accomplish this, the scientists analyzed gene expression in immune cells from brain samples of deceased Alzheimer’s patients and mouse models, comparing them to non-Alzheimer’s controls.

These comparisons revealed significant alterations in microglial gene expression due to Alzheimer’s, with an increase in PU.1’s binding to inflammatory gene targets being a notable part of these changes.

In addition, the team demonstrated that decreasing PU.1 activity in an Alzheimer’s mouse model led to reductions in both inflammation and neuronal death.

Senior author Dr. Li-Huei Tsai, Picower professor of neuroscience at MIT and director of The Picower Institute and MIT’s Aging Brain Initiative spoke to Medical News Today, saying that “we performed a small molecule screen against a factor, PU.1, that activates genes involved in inflammatory response.”

“Increased activity of this factor increases the risk of developing Alzheimer’s dementia. We demonstrated that our top hit, A11, reduced neuroinflammation, and Alzheimer’s related pathology in multiple Alzheimer’s mouse models and improved their cognitive function,” Dr. Tsai explained.

A11 was further assessed in cell models that mimic human brain immune cells, made from patient-derived stem cells.

A11 significantly reduced cellular inflammation and stress markers, making the cells act more like Healthy ones.

A11 works by “shifting” PU.1’s role from a gene “activator” to a “silencer,” offering a novel avenue for controlling neuroinflammation in Alzheimer’s.

The research team extended their investigation of A11’s efficacy to mouse models with Alzheimer’s-like symptoms. Initially, pharmacokinetic studies confirmed A11’s favorable brain penetrance and retention, a critical factor for CNS-targeted therapeutics.

Three mouse models representing different Alzheimer’s-associated pathologies were studied.

Encouragingly, A11 treatment led to reduced neuroinflammation, diminished neuronal death, and even showed positive changes in memory-related brain regions.

To assess cognitive function, the mice underwent maze-based memory tests.

Mice treated with A11 significantly outperformed the control group in tasks like locating a hidden platform in water, suggesting enhanced learning and memory skills.

Dr. J. Wes Ulm, not involved in this research, told MNT that this study “represents a preliminary though intriguing finding regarding a potentially innovative treatment approach to forestall and mitigate the onset of Alzheimer’s disease, alongside other forms of dementia and neurological illness.”

“The pathophysiology (chain of events leading to diagnosable illness) for dementia is multifactorial, but neuroinflammation — that is, inflammatory processes affecting neurons and their supportive cells, called glia — has been found to be associated frequently with an earlier and more pronounced disease presentation.”

– Dr. J. Wes Ulm

Dr. Ulm added that “several cellular pathways have been correlated with a higher incidence and extent of neuroinflammation, including one involving a protein called PU.1.”

Dr. Ulm explained that these “proteins act as so-called transcription factors, meaning that they help to activate the series of molecular steps in a cell’s nucleus through which a gene — a segment of DNA encoding a specific protein or family of proteins — is expressed to make a transcript (copy) of itself via another related molecule, called messenger RNA (mRNA).”

“This mRNA transcript is then translated into a protein which carries out cellular functions, and it turns out that in mice with a higher propensity toward developing neurodegenerative disease, PU.1 has an elevated proclivity to bind and activate targets on the DNA,” Dr. Ulm said.

“The researchers here were able to find an antagonist molecule, called A11, which helps to counteract PU.1 activity and appears to lessen the onset of disease,” he noted.

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