Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains
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Previous reports have shown that individual neurons of the brain can display somatic genomic mosaicism of unknown function. In this study, we report altered genomic mosaicism in single, sporadic Alzheimer's disease (AD) neurons characterized by increases in DNA content and amyloid precursor protein (APP) gene copy number. AD cortical nuclei displayed large variability with average DNA content increases of ∼8% over non-diseased controls that were unrelated to trisomy 21. Two independent single-cell copy number analyses identified amplifications at the APP locus. The use of single-cell qPCR identified up to 12 copies of APP in sampled neurons. Peptide nucleic acid (PNA) probes targeting APP, combined with super-resolution microscopy detected primarily single fluorescent signals of variable intensity that paralleled single-cell qPCR analyses. These data identify somatic genomic changes in single neurons, affecting known and unknown loci, which are increased in sporadic AD, and further indicate functionality for genomic mosaicism in the CNS.
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Additional somatic mutations in genes known to confer risk for AD such as APP and SORL1 have been identified in the brains of both EOAD and LOAD patients.
“Additional somatic mutations in genes known to confer risk for AD such as APP and SORL1 [237] have been identified in the brains of both EOAD and LOAD patients [238, 239]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [238]
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“Additional somatic mutations in genes known to confer risk for AD such as APP and SORL1 (Nicolas et al., 2018) have been identified in the brains of both EOAD and LOAD patients (Bushman et al., 2015; Sala Frigerio et al., 2015).”
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- Authors
- Bushman, D. M., Kaeser, G. E., Siddoway, B., Westra, J. W., Rivera, R. R., Rehen, S. K., Yung, Y. C., & Chun, J.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Chun, Jerold
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-02-04
- Volume
- 4
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4337608
- OpenAlex
- W2007326275
- Cited by
- 136
- References
- 87
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 5 · 2022: 15 · 2021: 13 · 2020: 19 · 2019: 17 · 2018: 19 · 2017: 11 · 2016: 8 · 2015: 8
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (MH076145, T32 DA07315, T32 AG 000216)
- Shaffer Family Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- sporadic Alzheimer's disease, amyloid precursor protein, single neurons, peptide nucleic acid probes, super-resolution microscopy
- MeSH terms
- Alzheimer Disease, Cell Nucleus, Cerebral Cortex, DNA, Down Syndrome, Flow Cytometry, Gene Amplification, Humans, Mosaicism, Neurons, Amyloid beta-Protein Precursor, Genome, In Situ Hybridization, Fluorescence, Gene Dosage, Peptide Nucleic Acids, Genetic Loci
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