The pathogenesis of Alzheimer's disease (AD) is believed to involve the accumulation of amyloid-β in the brain, which is produced by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase. Recently, analysis of genomic DNA and mRNA from postmortem brain neurons has revealed intra-exonic recombinants of APP (gencDNA), which have been implicated in the accumulation of amyloid-β. In this study, we computationally analyzed publicly available sequence data (SRA) using probe sequences we constructed to screen APP gencDNAs. APP gencDNAs were detected in SRAs constructed from both genomic DNA and RNA obtained from the postmortem brain and in the SRA constructed from plasma cell-free mRNA (cf-mRNA). The SRA constructed from plasma cf-mRNA showed a significant difference in the number of APP gencDNA reads between SAD and NCI: the p-value from the Mann-Whitney U test was 5.14 × 10. The transcripts were also found in circulating nucleic acids (CNA) from our plasma samples with NGS analysis. These data indicate that transcripts of APP gencDNA can be detected in blood plasma and suggest the possibility of using them as blood biomarkers for Alzheimer's disease.
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http://dx.doi.org/10.1038/s41598-023-48993-7 | DOI Listing |
Sci Rep
December 2023
Laboratory of Human Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, 411-8540, Japan.
Front Genet
May 2020
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
The recent identification of somatic gene recombination(SGR) in human neurons affecting the well-known Alzheimer's disease (AD) pathogenic gene, amyloid precursor protein (APP), has implications for the normal and the diseased human brain. The amyloid hypothesis has been the prevailing theory for sporadic AD (SAD) pathogenesis since the discovery of gene involvement in familial AD and Down syndrome. Yet, despite enormous scientific and clinical effort, no disease-modifying therapy has emerged.
View Article and Find Full Text PDFJ Exp Neurosci
May 2019
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
A first example of somatic gene recombination (SGR) within the human brain was recently reported, involving the well-known Alzheimer's disease (AD)-related gene amyloid precursor protein (). SGR was characterized by the creation of genomic complementary DNA (gencDNA) sequences that were identified in prefrontal cortical neurons from both normal and sporadic Alzheimer's disease (SAD) brains. Notably, SGR in SAD appeared to become dysregulated, producing many more numbers and forms of gencDNAs, including 11 single-nucleotide variations (SNVs) that are considered pathogenic mutations when they occur in families, yet are present mosaically among SAD neurons.
View Article and Find Full Text PDFProtein Sci
July 2019
Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37240.
The role of the amyloidogenic pathway in the etiology of Alzheimer's disease (AD), particularly the common sporadic late onset forms of the disease, is controversial. To some degree, this is a consequence of the failure of drug and therapeutic antibody trials based either on targeting the proteases in this pathway or its amyloid end products. Here, we explore the formidable complexity of the biochemistry and cell biology associated with this pathway.
View Article and Find Full Text PDFThe diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here we describe recombination of the Alzheimer's disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant 'genomic cDNAs' (gencDNAs).
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