A water pill may stave off Alzheimer’s by targeting genes responsible for the condition

 

• Research suggests that Alzheimer’s disease results from a combination of genetic, lifestyle, and environmental factors.
• Using mice models and human cell lines, scientists recently investigated potential therapeutic treatments for individuals with a genetic risk of developing Alzheimer’s disease.
• Their results indicate that bumetanide, which is a commonly available oral diuretic drug, has a significant therapeutic response in treating the neurodegenerative condition.
• The scientists conclude that bumetanide may one day become a potential treatment and prevention option for Alzheimer’s disease.

There is currently no known cureTrusted Source for Alzheimer’s disease.

Studies suggestTrusted Source that this is because the neurodegenerative condition results from complex interactions between several genetic, lifestyle, and environmental factors. Consequently, this has led to challenges in developing a single drug to treat every case of Alzheimer’s disease.

One studyTrusted Source suggests that the precision medicine approach may be a useful way to scale the drug discovery hurdle.

In precision medicine, disease treatment and prevention account for individual variations in genes, environment, and lifestyle and accommodate personalization based on the factors that may affect response to treatment.

Recently, scientists in the United States employed the precision medicine approach in targeting specific genes that increase the risk of developing Alzheimer’s disease. The aim was to investigate potential therapeutic options for the treatment of the neurodegenerative condition.

The results from their study appear in the journal Nature AgingTrusted Source.

Testing an APOE4 hypothesis

Corresponding study author Dr. Marina Sirota, Ph.D. — an associate professor at the Bakar Computational Health Sciences Institute (BCHSI) of the University of California, San Francisco (UCSF) — explained to Medical News Today the rationale behind their study.

Dr. Sirota said, “[W]e agnostically queried [Alzheimer’s] disease gene expression (whether certain genes are turned on or turned off) against a database of FDA-approved drugs to see which compounds might reverse the disease effects back to the normal state.”

“Here specifically, we take a precision medicine approach by focusing on individuals who have the APOE4/4 genotype as a starting point,” she explained.

“Bumetanide was one of our top hits using this computational approach, which led us to investigate this drug further,” Dr. Sirota concluded.

In this study, the researchers hypothesized that drugs that reverse the expression of differentially expressed genes in disease states toward normal levels may be beneficial against the condition.

First, the scientists chose the APOE genotype. This is the gene with the greatest risk factor for developing late-onset Alzheimer’s disease.

Next, they analyzed brain tissue samples from people with Alzheimer’s disease to identify the APOE gene expression signatures — that is, the extent to which genes are turned on or off because of the APOE genotype carriers.

Using a drug repurposing software, the team compared these signatures against a database of more than 1,300 FDA-approved drugs.

Here, bumetanide emerged as a suitable candidate for reversing APOE4-related expressions back to normal levels in individuals with Alzheimer’s disease.

The researchers then employed human cell lines, mice models, and electronic health records (EHRs) for real-world validation of these data. They genetically modified the brains of the rodents to produce APOE4-like symptoms, and they then treated the animals with bumetanide.

Over time, the scientists subjected the genetically modified animals to learning and behavioral tests for cognitive functions, and they noted the corresponding results.

In addition to the cognitive tests, the researchers harvested brain slices from the animals to explore the mechanism of action of bumetanide.

To extend the study to human tissues, the team genetically derived APOE4 neurons from the skin cells of an individual with the APOE4 genotype. The genetically “reprogrammed” cells are known as induced pluripotent stem cells (iPSCTrusted Source), and the ability of cells to do this is called pluripotencyTrusted Source.

The scientists treated the iPSC-derived human neurons with bumetanide, and they also noted these corresponding results.

Also, the researchers measured all test results against a control group.

Exciting results

The researchers discovered that in the brains of the genetically modified animals, bumetanide significantly reversed the APOE4 signature genes.

They also observed that in the brains of these animals, bumetanide improved memory formation and restored the ability of neurons to respond to stimuli by reorganizing their function and connections. These processes are known as neuronal excitability and plasticity, respectively.

During the behavioral tests, the researchers noted that study mice with learning deficits showed great improvements.

Furthermore, in the iPSC-derived human neurons, the scientists noticed a reversal in APOE4 signature genes similar to those of the bumetanide-treated, genetically modified animals.

Further studies revealed that human and rodent brain cells share three similar signature pathways for expressing the APOE4 gene. This suggests an explanation for how bumetanide elicits its effects.

Using EHRs from the UCSF and the Mount Sinai Health System, the scientists further tested the real-world efficacy of bumetanide.

They confirmed that those with exposure to bumetanide treatment had a significantly lower prevalence of Alzheimer’s disease than people without exposure to bumetanide treatment.

All these findings led the scientists to conclude that bumetanide may be effective in preventing Alzheimer’s disease.

To understand the implication of these results, MNT reached out to experts.

Dr. Jean Yuan, Ph.D.Trusted Source, program director for the Translational Bioinformatics Program at the National Institute on Aging, had a hopeful take on the study results.

Study limitations and conclusions

The study has several limitations. Firstly, because of the limited database for the APOE4 genotype, the sample size the researchers used was restricted to only one dataset containing 213 samples.

Secondly, the efficacy of bumetanide was validated only among the top predicted drugs in animal models and human EHR databases.

Lastly, the two EHR databases the scientists used in this study did not contain APOE genotype information, which means that further studies are now necessary.

Nevertheless, the study results spell exciting possibilities for the potential future treatment of Alzheimer’s disease.

Source: Medical News Today