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Alzheimer's disease (AD) is a progressive neurodegenerative disease, but the specific events leading to neuronal dysfunction and death remain poorly understood
A team of researchers from Boston Children's Hospital, the Broad Institute, Harvard Medical School and other institutions recently used single-cell sequencing technology to find an increase in somatic mutations in brain cells of patients with Alzheimer's disease
The paper, "Somatic genomic changes in single Alzheimer's disease neurons," was published April 20 in the journal Nature
Co-first author Michael Miller, a pathology researcher at Brigham and Women's Hospital, said: "Our findings suggest that AD neurons experience genomic damage that can place enormous stress on the cell and cause dysfunction
The researchers used single-cell whole-genome sequencing to analyze pyramidal neurons from nine Alzheimer's patients, as well as frozen autopsy brain samples from 20 controls
"Our findings suggest that the pathogenic mechanism of Alzheimer's disease may lead to genomic damage in neurons that progressively impairs their function," Miller and the other authors wrote
In fact, Miller noted, "the vast amount of oxidative damage and somatic mutations we observed in neurons" may have contributed to the pathology of the disease
In follow-up experiments, they used immunofluorescence microscopy to track 8-oxoG, a marker of oxidative stress, and found results that supported their idea
The researchers believe that excitatory neurons in the brains of Alzheimer's patients accumulate genomic damage, and possibly permanent mutations, beyond levels that accumulate in general aging
The authors caution that the current findings reflect the characteristics of patients with advanced Alzheimer's disease at death, while samples from intermediate-stage patients remain to be studied with single-cell sequencing methods
Collectively, the results of these analyses will help researchers understand the biology behind Alzheimer's disease and reveal more alterations and mechanisms that will hopefully lead to new therapeutic strategies and targets
"We wanted to elucidate how the mutations observed in Alzheimer's neurons lead to neuronal cell death," Miller said
Original text retrieval
Miller, MB, Huang, AY, Kim, J.