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

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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Rao CV,Asch AS,Carr DJJ,Yamada HY

doi

10.1111/acel.13109

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

e13109

issue

3

eissn

1474-9718

issn

1474-9726

journal_volume

19

pub_type

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