Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer’s Disease and Brain Insulin Resistance, and Its Relation to Cancer

Article type: Review Article

Authors: Koseoglu, Mehmet Murat^{a; *} | Norambuena, Andrés^b | Sharlow, Elizabeth R.^a | Lazo, John S.^{a; c; d} | Bloom, George S.^{b; e; f; *}

Affiliations: [a] Department of Pharmacology, University of Virginia, Charlottesville, VA, USA | [b] Department of Biology, University of Virginia, Charlottesville, VA, USA | [c] Department of Chemistry, University of Virginia, Charlottesville, VA, USA | [d] Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA | [e] Department of Cell Biology, University of Virginia, Charlottesville, VA, USA | [f] Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

Correspondence: [*] Correspondence to: George S. Bloom, Department of Biology, University of Virginia, PO Box 400328, Charlottesville, VA 22904-4328, USA. Tel.: +1 434 243 3543; E-mail: [email protected] and Mehmet Murat Koseoglu, Department of Pharmacology, University of Virginia, PO Box 800735, Charlottesville, VA 22908-0735, USA. Tel.: +1 434 924 2466; E-mail: [email protected].

Abstract: Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer’s disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling “hotspots” in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD.

Keywords: Alzheimer’s disease, amyloid, cell cycle re-entry, tau

DOI: 10.3233/JAD-180874

Journal: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 1-11, 2019