Abstract
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 APP gene involvement in familial AD and Down syndrome. Yet, despite enormous scientific and clinical effort, no disease-modifying therapy has emerged. SGR offers a novel mechanism to explain AD pathogenesis and the failures of amyloid-related clinical trials, while maintaining consistency with most aspects of the amyloid hypothesis and additionally supporting possible roles for tau, oxidative stress, inflammation, infection, and prions. SGR retro-inserts novel “genomic complementary DNAs” (gencDNAs) into neuronal genomes and becomes dysregulated in SAD, producing numerous mosaic APP variants, including DNA mutations observed in familial AD. Notably, SGR requires gene transcription, DNA strand-breaks, and reverse transcriptase (RT) activity, all of which may be promoted by well-known AD risk factors and provide a framework for the pursuit of new SGR-based therapeutics. In this perspective, we review evidence for APP SGR in AD pathogenesis and discuss its possible relevance to other AD-related dementias. Further, SGR’s requirement for RT activity and the relative absence of AD in aged HIV -infected patients exposed to RT inhibitors suggest that these Food and Drug Administration (FDA)-approved drugs may represent a near-term disease-modifying therapy for AD.
Highlights
somatic gene recombination (SGR) may act as a form of cellular memory (Crick, 1984; Davis and Squire, 1984), where transcriptional activity and resulting DNA breaks may enable the retro-insertion of genomic complementary DNA (gencDNA) ready for reexpression as pre-spliced and varied mRNAs and diverse protein products: a form of long-lasting memory
The dysregulation of SGR produces disease through increased numbers and forms of toxic gencDNAs, as illustrated by somatic, genomic changes documented in sporadic AD (SAD) brains
The SGR hypothesis in Alzheimer’s disease (AD) does not reject the amyloid hypothesis outright but rather incorporates major features to modify the hypothesis while accommodating other distinct hypotheses and explaining discrepancies in the scientific and clinical trial literature through the generation of amyloid precursor protein (APP) variants and downstream molecular diversity
Summary
SGR offers a novel mechanism to explain AD pathogenesis and the failures of amyloid-related clinical trials, while maintaining consistency with most aspects of the amyloid hypothesis and supporting possible roles for tau, oxidative stress, inflammation, infection, and prions. SGR requires gene transcription, DNA strand-breaks, and reverse transcriptase (RT) activity, all of which may be promoted by well-known AD risk factors and provide a framework for the pursuit of new SGR-based therapeutics. In this perspective, we review evidence for APP SGR in AD pathogenesis and discuss its possible relevance to other AD-related dementias.
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