title: Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains.
abstract: 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.
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Diane M
authors: DM
authors: Bushman
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Gwendolyn E
authors: GE
authors: Kaeser
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Benjamin
authors: B
authors: Siddoway
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Jurgen W
authors: JW
authors: Westra
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Richard R
authors: RR
authors: Rivera
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Stevens K
authors: SK
authors: Rehen
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Yun C
authors: YC
authors: Yung
authors: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.
authors: Jerold
authors: J
authors: Chun
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D004247:DNA / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics; D005434:Flow Cytometry; D005784:Gene Amplification; D018628:Gene Dosage; D056426:Genetic Loci; D016678:Genome; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009030:Mosaicism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020135:Peptide Nucleic Acids / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D020135:Peptide Nucleic Acids; D004247:DNA
keywords: AD; CNV; amyloid precursor protein; human; neuroscience; somatic mosaicism
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