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Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer's Disease.

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.

SUBMITTER: Kaeser GE

PROVIDER: S-EPMC7221065 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer's Disease.

Kaeser Gwendolyn E GE Chun Jerold J

Frontiers in genetics 20200507

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 <i>APP</i> gene involvement in familial AD and Down syndrome. Yet, despite enormous scientific and clinical effort, no disease-modifying therapy has ...[more]

PMID: 32457796

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Project description:Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-? protein (A?), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive A? accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking A? and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by A?-amyloid deposits (A? oligomers and plaques) not only drives A? aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal A? deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal A? amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on ?-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

Dataset Information

Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer's Disease.

Publications

Mosaic Somatic Gene Recombination as a Potentially Unifying Hypothesis for Alzheimer's Disease.

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