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Alzheimer’s may increase DNA variants in brain neurons

DNA mutation

Neurons in the brains of people with Alzheimer’s disease accumulate more DNA changes, called somatic variants, and these changes differ from those found in individuals without the disease. The findings from this NIA-funded study, published in Nature, suggest a link between genomic damage to neurons and the development of pathological hallmarks of Alzheimer’s.

A team of researchers at Brigham and Women’s Hospital and Boston Children’s Hospital used advanced DNA sequencing technologies to analyze neurons from postmortem brain tissue donated by people with Alzheimer’s and others of the same age without the disease. Specifically, they searched for changes in chromosomal DNA called somatic single nucleotide variants. A cell’s chromosomal DNA is made of four building block molecules, called nucleotides, strung together in rows like beads on a string. Just as letters spell words, nucleotide sequences spell the codes for genes. Somatic single nucleotide variants represent single-letter changes to chromosomal DNA that may happen over a lifetime. They may occur when DNA is damaged by environmental exposures, such as sunlight or reactive chemicals produced by the body.

The researchers discovered that, on average, neurons found in the brains of people who died with Alzheimer’s had more variants than neurons from individuals of the same age who did not have the disease. Further analysis suggested that high levels of oxidative stress caused by Alzheimer’s may have triggered the changes. Here, oxidizing chemicals in the brain may have reacted and damaged neuronal chromosomes. In turn, this damage may hamper a cell’s natural ability to repair changes, resulting in more variants. Many of the variants appeared in genes known to play a central role in the lives of neurons. The researchers predict that these variants may result in dysfunctional proteins that could impair neuron survival and brain function.

This study provides a detailed look at the DNA changes in individual neurons affected by Alzheimer’s and insight into the processes contributing to these changes. A better understanding of these processes may provide new targets for developing drugs or other strategies to slow or prevent Alzheimer’s.

This research was supported in part by NIA grants K08AG065502, R00AG054748, K01AG051791, DP2AG072437, R01AG070921, and 1P30AG062421-01.

These activities relate to NIH’s Alzheimer’s and Related Dementias Research Implementation Milestone 2.C, “Create research programs on epigenetics to understand how genetic and environmental factors interact across the lifespan to influence brain aging and risk for disease and to identify potential targets for treatment and prevention.”

Reference: Miller MB, et al. Somatic genomic changes in single Alzheimer’s disease neurons. Nature. 2022;604(7907):714-722. doi: 10.1038/s41586-022-04640-1.

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