Diuretic against Alzheimer's
The development of drugs for the treatment of Alzheimer's disease is very slow. Researchers from the Gladstone Institutes, the University of California at San Francisco, and the Icahn School of Medicine at Mount Sinai have found that the diuretic bumetanide, used for more than 30 years to treat edema and heart failure, eliminates signs of Alzheimer's disease in mice, as well as in vitro in human brain cells. Analysis of case histories from two independent institutions showed that patients over 65 years of age who took bumetanide were less likely to develop Alzheimer's disease than the rest.
An alternative approach to finding medicines
The development of new drugs for the treatment of complex diseases such as Alzheimer's disease is a long and expensive process. In 2017, in order to provide safer treatments more quickly, Gladstone Institutes launched a project to repurpose already used drugs for new purposes.
This strategy is based on the hypothesis that neurodegeneration may occur for different reasons in different patients with Alzheimer's disease, and, therefore, the effectiveness of specific treatment methods may differ. In this study, the team used a computational method to identify a unique expression profile of genes associated with Alzheimer's disease in brain tissues in certain subgroups of patients. Then the scientists went through the database of existing drugs to find those that are most likely to affect the altered gene expression in each subgroup.
An amazing candidate
The new study analyzed 213 brain samples of people from a publicly available database with and without Alzheimer's disease, including carriers of various versions of the APOE gene, the main genetic risk factor for the disease.
The team identified changes in the expression of almost 2,000 genes in the brains of people with Alzheimer's disease. Approximately 6% of the altered genes were similar in people with different versions of APOE, the vast majority of them were unique to people with specific combinations of APOE3 or APOE4 versions, with the latter causing the highest genetic risk of Alzheimer's disease.
The researchers then queried a database of more than 1,300 existing drugs to find those capable of influencing altered gene expression identified for subgroups of Alzheimer's patients. Five of the best drugs that can restore the expression of genes associated with Alzheimer's disease in people carrying two copies of the APOE4 version have been selected.
The best of the five candidate drugs turned out to be bumetanide, a diuretic that affects the absorption of sodium and chlorides by cells. These ions are important not only for maintaining fluid levels throughout the body, but also for transmitting electrical signals between neurons in the brain.
The path to practice
The researchers tested the effect of bumetanide on genetically modified mice expressing the human protein APOE. In mice with two copies of the human version of the APOE4 gene, learning and memory deficits developed at the age of 15 months, which is equivalent to about 60 years in humans. But when the researchers injected the mice with bumetanide, they no longer developed such a deficiency. In addition, the drug caused changes in the electrical activity of the brain, which may underlie these cognitive impairments.
Scientists have also created another mouse model of Alzheimer's disease, in which two copies of APOE4 are combined with amyloid plaques in the brain – the main pathological sign of Alzheimer's disease. In these mice, treatment with bumetanide led to a decrease in the accumulation of amyloid plaques and the restoration of normal brain activity.
Finally, when the researchers studied the effect of the drug on human neurons grown from skin cells of Alzheimer's patients carrying the APOE4 gene, they found that bumetanide reversed the changes in gene expression associated with the disease.
As part of the study, the authors analyzed two large databases of electronic medical records and selected 3,700 patients over the age of 65 who took bumetanide. They were compared with patients of similar age and health status who took other diuretics. Strikingly, patients taking bumetanide were 35-75% less likely to be diagnosed with Alzheimer's disease.
The authors plan clinical trials of bumetanide on people suffering from Alzheimer's disease, especially carriers of APOE4. In parallel, the group is also studying other drugs that, as shown by computational analysis, change the expression of genes associated with Alzheimer's disease associated with APOE.
Article A.Taubes et al. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease is published in the journal Nature Aging.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru according to Gladstone Institutes: Can an Already Approved Drug Treat Alzheimer's Disease?