- Scientists have taken a significant step toward addressing brain inflammation in Alzheimer’s, which has the potential to reduce symptom severity.
- A recent 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, A11 inhibits the gene’s ability to promote inflammation in the brain.
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.
A preliminary study published in the Journal of Experimental Medicine reveals that a molecule effectively reduced inflammation in cells similar to human microglia and also in several Alzheimer’s mouse models.
The molecule also notably enhanced cognitive function in the mice.
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.
In this research, the team sought to address Alzheimer’s-associated inflammation modulated by the protein PU.1, which is crucial for many physiological processes.
Targeting PU.1 directly is not feasible due to its role in normal bodily functions.
Therefore, the team screened over 58,000 chemical compounds to find those capable of mitigating PU.1-driven inflammation in Alzheimer’s without affecting PU.1 levels.
After rigorous testing, six candidate compounds were identified, with A11 being the most effective.
“This study demonstrated that identifying drugs against PU.1 could be a viable approach to treat neuroinflammatory diseases including Alzheimer’s disease.”
— Dr. Li-Huei Tsai, senior study author
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, a physician-researcher 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, physician-researcher
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.
Dr. Ulm explained how dementia continues to be among the most challenging types of diseases to manage, causing significant emotional and physical burden on those affected, as well as their families and caregivers.
This is evident in metrics like the number of disability-adjusted life years (DALYs) that are lost per year die to dementia the United States.
While there has been a slight decline in the rate of new dementia cases in recent years — even accounting for the recent drop in life expectancy in the U.S. — Alzheimer’s remains an expensive and complex medical condition with limited treatment options to alter or improve its progression.
“If further research bears out the findings as ascertained in this report, it might open up the possibility of treatment through a new class of therapeutic candidates that, alone or in combination with other drugs and interventions, may help to enhance quality of life and reduce the early onset and severity of dementia and related disease classes.”
– Dr. J. Wes Ulm, physician-researcher