Researchers at the Picower Institute at MIT have unveiled a promising candidate drug, known as A11, aimed at mitigating the inflammatory response in the brain, thereby reducing the pathology of Alzheimer’s disease, safeguarding neurons, and bolstering cognitive function, as demonstrated in preclinical trials.
While some medications have made progress in tackling Alzheimer’s by targeting the amyloid-beta protein, other facets of the disease, notably inflammation, have remained a challenge. In a recent study, scientists from MIT’s Picower Institute for Learning and Memory introduced A11, a potential drug that not only reduces inflammation but also enhances memory in human cell cultures and Alzheimer’s mouse models.
The Key Target: PU.1
A critical focus of the A11 molecule is a genetic transcription factor called PU.1. Previous research has shown that during Alzheimer’s disease, PU.1 becomes overly active in directing the expression of inflammatory genes in the brain’s microglia immune cells. A11, as the new research indicates, effectively suppresses this problematic PU.1 activity by recruiting other proteins that inhibit the expression of inflammatory genes regulated by PU.1. Importantly, A11 primarily targets the brain, leaving PU.1’s other role, ensuring the production of various blood cells, unaffected.
Addressing Inflammation in Alzheimer’s
“Inflammation is a major component of Alzheimer’s disease pathology that has been especially hard to treat,” says Li-Huei Tsai, 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 study, recently published in the Journal of Experimental Medicine, has Li-Huei Tsai and Elizabeta Gjoneska of the National Institutes of Health as co-corresponding authors.
Building on Previous Insights
This research builds upon earlier work that identified PU.1’s role in regulating microglia inflammation in Alzheimer’s disease. The quest to find a safe method to restore PU.1 to healthy levels has been ongoing since then.
The new study, led by William Ralvenius, a research scientist at the Picower Institute, began with experiments to confirm PU.1’s significance as a therapeutic target. Gene expression comparisons in immune cells from postmortem brain samples of Alzheimer’s patients and mouse models, along with non-Alzheimer’s controls, showed substantial changes in microglial gene expression during Alzheimer’s. Notably, the increased binding of PU.1 to inflammatory gene targets was a significant part of this change. Reducing PU.1 activity in a mouse model of Alzheimer’s led to reduced inflammation and neurodegeneration, a decline in neuron health.
The Screening Process and Outcomes
Genetically suppressing PU.1 throughout the body is not a viable treatment strategy due to its essential role in healthy bodily functions. Therefore, researchers screened over 58,000 small molecules from FDA-approved drug libraries and novel chemicals to identify substances that could safely and effectively reduce key inflammatory and Alzheimer’s-related genes regulated by PU.1 in cell cultures. After rigorous screening, A11 emerged as the most potent candidate.
Testing A11 on human microglia-like cells cultured from patient stem cells revealed reduced expression and secretion of inflammatory cytokines when exposed to typical inflammatory triggers. Additionally, the cells displayed less inflammation-associated shape changes and reduced accumulation of lipid molecules. Gene expression patterns indicated that A11-treated cells responded similarly to unperturbed microglia when exposed to inflammatory cues, suggesting A11 prevents excessive microglial reactions to inflammation triggers.
Mechanism of Action
Further tests unveiled that A11 does not alter PU.1 levels; instead, it counteracts PU.1 activity by recruiting various proteins, including MECP2, HDAC1, SIN3A, and DMNT3A, known for repressing the expression of PU.1’s target genes. Essentially, A11 moderates what PU.1 exacerbates, establishing a controlled state of microglial inflammation amid Alzheimer’s disease.
Efficacy in Mouse Models
Pharmacological evaluations demonstrated that A11 is efficiently eliminated from tissues and can reach brain cells. In healthy mice, it traversed the blood-brain barrier and remained in brain cells longer than in other tissues.
Subsequently, the researchers tested A11’s effects on Alzheimer’s pathology and symptoms in three mouse strains, each modeling different aspects of the disease. A11 treatment in CK-p25 mice and Tau P301S transgenic mice reduced inflammatory responses among microglia and astrocyte cells, preserving more neurons. TauP301S Tg mice exhibited a significant reduction in phosphorylated tau protein, essential for memory, in the hippocampus region of the brain. In 5XFAD mice, amyloid accumulation was notably diminished.
Enhanced Cognitive Function
To assess cognitive function, researchers subjected Tau P301S Tg and CK-p25 mice to mazes designed to evaluate short-term working memory and long-term learning. In both models and tests, A11-treated mice outperformed untreated counterparts. For instance, in the “Morris Water Maze,” which assesses spatial memory, treated CK-p25 mice displayed accelerated learning compared to untreated mice.
More Testing Ahead
While A11 shows promise, further rigorous testing is imperative before it can gain approval as a treatment. Nevertheless, it could complement existing therapies that target amyloid, offering enhanced options for neurodegenerative diseases.
Funding for this research was provided by The Robert A. and Renee E. Belfer Family Foundation, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory, The Halis Family Foundation, Lester A. Gimpelson, Jay L. Miller, and Caroll Miller.
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Frequently Asked Questions (FAQs) about Alzheimer’s Drug
What is the A11 drug mentioned in the article?
The A11 drug is a candidate medication developed by researchers at MIT’s Picower Institute for Learning and Memory. It aims to combat inflammation in the brain associated with Alzheimer’s disease and enhance cognitive function.
How does the A11 drug work to reduce inflammation?
The A11 drug targets a genetic transcription factor called PU.1, which becomes overactive during Alzheimer’s disease, promoting the expression of inflammatory genes in microglia immune cells. A11 suppresses this activity by recruiting other proteins that inhibit the expression of these inflammatory genes, thus reducing inflammation.
What are the potential benefits of the A11 drug?
The A11 drug has shown promise in preclinical trials by reducing Alzheimer’s-related inflammation, preserving neurons, and enhancing cognitive function in mouse models. It may offer a new avenue for Alzheimer’s treatment.
Has the A11 drug been tested on humans yet?
As of the article’s publication, the A11 drug had undergone preclinical trials, primarily using cell cultures and mouse models. Further testing and clinical trials are required before it can be considered for human use.
How does A11 compare to existing Alzheimer’s treatments?
A11 operates via a distinct mechanism from existing Alzheimer’s therapies, which primarily target amyloid. It could potentially be used alone or in combination with current treatments to provide more comprehensive options for neurodegenerative diseases.
Who funded the research on the A11 drug?
The research on the A11 drug received funding from The Robert A. and Renee E. Belfer Family Foundation, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory, The Halis Family Foundation, Lester A. Gimpelson, Jay L. Miller, and Caroll Miller.
1 comment
Need more proofreading, grammar mistakes here and there. Otherwise, informative.