In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
Abstract:
Alzheimer’s disease (AD) is characterized pathologically by deposition of misfolded amyloid‐b and tau proteins. However, protein‐directed therapeutic strategies have shown limited clinical benefit, pointing to the need to examine pathogenesis from a broader lens. Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ∼15 sSNV per year. In AD, DNA damage is increased, with potentially significant effects on the genome of each cell. Method We performed single‐cell whole‐genome sequencing on neurons from postmortem brain tissue from humans with AD and age‐matched controls, using two independent genome amplification methods (MDA and PTA), and analyzed the burden of somatic mutations. We also performed mutational signature analysis of the nucleotide changes and trinucleotide context to assess for mutagenic patterns. Result We found significantly increased sSNV in AD, with each neuron carrying hundreds of additional somatic mutations, with a distinct mutation pattern. AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C 〉 A variants. We found elevated 8‐Oxoguanine DNA lesions, evidence that these mutations may result from oxidative damage to DNA. Mutations also show a mechanistic role for gene transcription in the generation of sSNV. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen‐stimulated immune attack. Conclusion Somatic mutations accumulate abundantly in Alzheimer’s disease, distributed across the genome. Our findings implicate multiple mutagenic forces in sSNV generation in AD, illuminating multiple upstream components of disease pathogenesis including DNA oxidation and transcription‐coupled DNA repair. Furthermore, elevated somatic mutation levels appear to produce a toxic cellular state, positioning neurons for dysfunction and death. These findings therefore identify somatic mutation accumulation as a novel process in neurodegeneration, through which we can dissect the cascade of events in Alzheimer’s disease pathogenesis.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2201940-6
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