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Advanced Alzheimer's Disease Linked to Somatic Mutation Rise in Neuronal Cells

NEW YORK – With the help of single-cell sequencing, a team from Boston Children's Hospital, the Broad Institute, Harvard Medical School, and elsewhere has found evidence for enhanced somatic mutation in brain cells from individuals with Alzheimer's disease — changes suspected of contributing to accelerated neuronal cell death in those with the neurodegenerative condition.

"Our results suggest that AD neurons experience genomic damage that causes immense stress on cells and creates dysfunction among them," co-first author Michael Miller, a pathology researcher at the Brigham and Women's Hospital, said in a statement. "These findings may explain why many brain cells die during [Alzheimer's disease]."

As they reported in Nature on Wednesday, the researchers used single-cell whole-genome sequencing to analyze pyramidal neurons in frozen post-mortem brain samples from individuals with or without Alzheimer's disease. Based on single-cell genome profiles for more than 300 hippocampal or prefrontal cortex neurons, they saw higher-than-usual levels of single nucleotide changes linked to oxidative stress and related DNA damage in cells from the Alzheimer's disease cases.

"Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function," Miller and his co-authors wrote. "The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease."

Indeed, Miller noted that the "sheer number of oxidative lesions and somatic mutations we observed" in Alzheimer's disease neurons may contribute to the pathology of the condition. Along with age-related mutational signatures, for example, he and his colleagues highlighted a signature that has been linked to the oxidation of nucleotides in DNA.

In follow-up experiments using immunofluorescence microscopy to track an oxidative stress-linked nucleotide lesion called 8-oxoguanine (8-oxoG), they found support for this idea, since individual neurons from Alzheimer's disease cases had significantly more 8-oxoG kicking around than did control neurons tested with the same approach.

"Our analysis reveals that excitatory neurons in the brains of individuals with AD accumulate genomic damage — and likely permanent mutations — beyond the levels that occur as a result of aging alone," the authors reported, adding that "[o]ther types of somatic alterations — such as short insertions and deletions — can also be explored in greater depth as technologies improve."

The authors also cautioned that the current findings reflect features found in individuals with advanced forms of Alzheimer's disease when they died, while samples from Alzheimer's disease patients at a more intermediate stage of the disease are yet to be studied with the single cell sequencing approach. They also pointed to the potential for incorporating additional RNA sequencing data to detect related structural variants in the individual neurons of individuals with Alzheimer's.

Together, the results from such analyses are expected to help in understanding the biology behind known Alzheimer's contributors, while uncovering further alterations and mechanisms that may lead to new treatment strategies and targets.

"[W]e are eager to elucidate how the observed mutations in [Alzheimer's disease] neurons cause neuronal cell death," Miller said, "and are dedicated to aiding in the discovery of novel treatments that target these pathways."

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