Specific enrichment of somatic single nucleotide variants in Alzheimer-associated tetraploid neurons
Year: 2026
Type: article
Abstract: An early pathological process observed in the brains of patients with Alzheimer's disease (AD) is the reactivation of the cell cycle in neurons, followed by somatic neuronal tetraploidization (NT). NT increases with age, and aging has been shown to correlate with the accumulation of DNA somatic mutations in neurons. In this study, we evaluated the presence of somatic mutations, including single nucleotide variants (SNVs) and short insertions or deletions (INDELs), in genomic DNA from tetraploid neurons obtained from the parietal cortex of patients with AD, as compared with diploid neurons from control individuals and patients with AD. Here we show that, in contrast to somatic INDELs, somatic SNVs (sSNVs) are significantly increased in the exome of tetraploid neurons, with elevated levels of T to C (A to G) transitions, a type of mutation associated with oxidative stress. This finding correlates with the overrepresentation of sSNVs in genes involved in the oxidative stress response and DNA repair, with DNA repair genes showing significantly enhanced molecular pathogenicity scores (MPS). Moreover, sSNVs affecting cancer- and senescence-related genes show a greater MPS than those from a random sample of genes. We propose a model in which neuronal tetraploidy may be stochastically triggered in neurons with mutated DNA repair genes under oxidative stress, potentially exacerbating oxidative DNA damage. This could facilitate cell cycle progression, followed by tetraploidization and senescence in the affected neurons, a process that may contribute to the pathogenesis of AD.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223132879