"Amyloid-beta accumulation cycle" as a prevention and/or therapy target for Alzheimer's disease.

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2020
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Abstract
The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad-spectrum anticancer drugs. Cyclin-dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA-approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid-beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD-omics and preclinical animal models provided data supporting the long-standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re-entry, leading to the "amyloid-beta accumulation cycle," may be a prerequisite for amyloid-beta accumulation and AD pathology development; (b) AD-associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the "amyloid-beta accumulation cycle is an AD drug target" concept is proven, repurposing of cancer drugs may emerge as a new, fast-track approach for AD management in the clinic setting.
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rao2020amyloidbetaaging Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Rao, Chinthalapally V;Asch, Adam S;Carr, Daniel J J;Yamada, Hiroshi Y;
Journal Aging cell
Year 2020
DOI
10.1111/acel.13109
URL
Keywords
brain mitosis mouse cell cycle alzheimer's disease (ad) shugoshin 1 (sgo1) amyloid-beta (aβ) chromosome instability (cin) cohesinopathy cyclin-dependent kinase (cdk) inhibitor

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