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

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.