Somatic genomic changes in single Alzheimer’s disease neurons

Michael B. Miller, August Yue Huang, Junho Kim, Zinan Zhou, Samantha L. Kirkham, Eduardo A. Maury, Jennifer S. Ziegenfuss, Hannah C. Reed, Jennifer E. Neil, Lariza Rento, Steven C. Ryu, Chanthia C. Ma, Lovelace J. Luquette, Heather M. Ames, Derek H. Oakley, Matthew P. Frosch, Bradley T. Hyman, Michael A. Lodato (), Eunjung Alice Lee () and Christopher A. Walsh ()
Additional contact information
Michael B. Miller: Brigham and Women’s Hospital, Harvard Medical School
August Yue Huang: Boston Children’s Hospital
Junho Kim: Boston Children’s Hospital
Zinan Zhou: Boston Children’s Hospital
Samantha L. Kirkham: Boston Children’s Hospital
Eduardo A. Maury: Boston Children’s Hospital
Jennifer S. Ziegenfuss: University of Massachusetts Chan Medical School
Hannah C. Reed: Boston Children’s Hospital
Jennifer E. Neil: Boston Children’s Hospital
Lariza Rento: Boston Children’s Hospital
Steven C. Ryu: Boston Children’s Hospital
Chanthia C. Ma: Boston Children’s Hospital
Lovelace J. Luquette: Harvard Medical School
Heather M. Ames: University of Maryland School of Medicine
Derek H. Oakley: Harvard Medical School, Massachusetts General Hospital
Matthew P. Frosch: Harvard Medical School, Massachusetts General Hospital
Bradley T. Hyman: Harvard Medical School, Massachusetts General Hospital
Michael A. Lodato: Boston Children’s Hospital
Eunjung Alice Lee: Boston Children’s Hospital
Christopher A. Walsh: Boston Children’s Hospital

Nature, 2022, vol. 604, issue 7907, 714-722

Abstract: Abstract Dementia in Alzheimer’s disease progresses alongside neurodegeneration1–4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer’s disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer’s disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles ‘clock-like’ mutational signatures that have been previously described in healthy and cancerous cells6–10. In neurons affected by Alzheimer’s disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer’s-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer’s disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer’s disease may lead to genomic damage to neurons that can progressively impair function. 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.

Date: 2022
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DOI: 10.1038/s41586-022-04640-1

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