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Inside brain cells, errors in DNA can accumulate as we age. But in patients with Alzheimer’s disease, these errors – known as somatic mutations – can accumulate at a faster rate.
A study by researchers at Brigham and Women’s Hospital and Boston Children’s Hospital found that patients with Alzheimer’s disease (AD) have a greater number of somatic mutations in their brain cells and that these mutations differ from those of people without Alzheimer’s disease. The team’s results are published in “Nature.”
“It is known that as we age, neurons accumulate somatic mutations. In AD neurons, however, we observed more mutations and alterations of DNA,” says lead author Michael B.
Miller. “Our results suggest that AD neurons experience a genomic damage which causes immense stress on the cells and creates a dysfunction between them. These findings could explain why many brain cells die during AD.”
The team conducted their study using single-cell whole genome sequencing of 319 neurons from the hippocampus and prefrontal cortex of patients with and without AD to determine the relationship between the number and type of somatic mutations and AD. To better understand the genomic changes that occur in AD neurons, the researchers sequenced DNA from the tissues and discovered a larger number of mutations called somatic single nucleotide variants (sSNVs) in patients with AD.
Theorizing that the large number of mutations is the result of increased DNA oxidation, the researchers then measured 8-Oxoguanine, an indicator of oxidative stress and DNA damage, and found that AD neurons agreed. made more rusty.
Ultimately, the discovery of the accumulation of DNA alterations in AD neurons provides researchers with a window into the molecular and cellular events in AD pathogenesis. “Our findings suggest that the large number of oxidative lesions and somatic mutations that we see in AD neurons may contribute to its pathology,” says Miller.
The authors acknowledge two main limitations of the study. Firstly, two groups were mainly studied: patients without neurological disease and those with advanced AD according to the system of braak staging. In the future, the researchers want to study neurons from individuals with mid-stage AD.
Second, although single-cell whole-genome sequencing was feasible for preliminary studies, the authors note that there are advanced methods that allow in-depth analysis of each DNA strand that should be explored in the future.
“In the future, we are eager to elucidate how the mutations observed in AD neurons cause cell death pathways and we are dedicated to aiding in the discovery of new treatments that target these pathways,” adds Miller.
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