Pathological implications of cell cycle re-entry in Alzheimer disease

Abstract

The complex neurodegeneration underlying Alzheimer disease (AD), although incompletely understood, is characterised by an aberrant re-entry into the cell cycle in neurons. Pathological evidence, in the form of cell cycle markers and regulatory proteins, suggests that cell cycle re-entry is an early event in AD, which precedes the formation of amyloid-beta plaques and neurofibrillary tangles (NFTs). Although the exact mechanisms that induce and mediate these cell cycle events in AD are not clear, significant advances have been made in further understanding the pathological role of cell cycle re-entry in AD. Importantly, recent studies indicate that cell cycle re-entry is not a consequence, but rather a cause, of neurodegeneration, suggesting that targeting of cell cycle re-entry may provide an opportunity for therapeutic intervention. Moreover, multiple inducers of cell cycle re-entry and their interactions in AD have been proposed. Here, we review the most recent advances in understanding the pathological implications of cell cycle re-entry in AD.

Figure 1. Cell cycle markers representing all stages of the cell cycle are ectopically expressed in neurons during Alzheimer disease

Phosphorylated p130 (pp130), a marker of G1 phase, is selectively increased in neurons in Alzheimer disease (AD) and therefore may not be able to prevent cell cycle reentry (Ref. 68). Phosphorylated retinoblastoma protein Rb (pRb), which is normally expressed during the G1-S transition, is present in nuclei, neurofibrillary tangles (NFTs) and other pathological structures (Ref. 69). CARB (CIP-1-associated regulator of cyclin B), a regulator of cyclin B in G2 phase, is also increased in NFTs (Ref. 70), as is BRCA1, an M-phase marker (Ref. 71). Reprinted from Ref. , with permission from Nova Science Publishers, Inc. © 2010

Figure 2. The two-hit hypothesis

An initial insult, whether oxidative or mitotic, that is chronic and above threshold limits leads to a new steady state (either oxidative steady state or mitotic steady state). It is in this new steady state when neurons are vulnerable to the subsequent second hit, which causes the Alzheimer disease phenotype. Reprinted from Ref. , with permission from Elsevier © 2004.