Somatic genomic changes in single Alzheimer's disease neurons

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is characterized by neurodegeneration, but the underlying causes of neuronal dysfunction and death are not fully understood.
• Neurons accumulate somatic mutations during normal aging, influenced by genetic and environmental factors.
• Understanding these mutations is crucial for deciphering AD pathogenesis.

Purpose of the Study:

• To investigate somatic DNA alterations in neurons from individuals with and without Alzheimer's disease.
• To identify distinct mutational patterns associated with AD.
• To explore the mechanisms driving genomic damage in AD neurons.

Main Methods:

• Single-cell whole-genome sequencing of 319 neurons from the prefrontal cortex and hippocampus.
• Analysis of somatic DNA alterations in neurons from Alzheimer's disease patients and neurotypical controls.
• In situ assessment of nucleotide oxidation in affected neurons.

Main Results:

• Neurons in Alzheimer's disease exhibit increased somatic DNA alterations compared to controls, with distinct molecular patterns (signature C) beyond age-related changes (signature A).
• Signature C involves specific nucleotide changes (e.g., C>A), suggesting a role for nucleotide oxidation, which was observed to be increased in AD neurons.
• Mutations affect coding regions, potentially leading to dysfunctional cells and proteostatic stress, with evidence suggesting transcription-coupled repair involvement.

Conclusions:

• Alzheimer's disease pathogenesis involves aberrant accumulation of DNA alterations in neurons, contributing to neurodegeneration.
• Genomic damage, potentially mediated by oxidative stress and influenced by transcription, plays a significant role in neuronal dysfunction and death in AD.
• These findings offer new insights into the molecular cascade of Alzheimer's disease development.