Cell cycle deregulation in the neurons of Alzheimer's disease

Abstract

The cell cycle consists of four main phases: G(1), S, G(2), and M. Most cells undergo these cycles up to 40-60 times in their life. However, neurons remain in a nondividing, nonreplicating phase, G(0). Neurons initiate but do not complete cell division, eventually entering apoptosis. Research has suggested that like cancer, Alzheimer's disease (AD) involves dysfunction in neuronal cell cycle reentry, leading to the development of the two-hit hypothesis of AD. The first hit is abnormal cell cycle reentry, which typically results in neuronal apoptosis and prevention of AD. However, with the second hit of chronic oxidative damage preventing apoptosis, neurons gain "immortality" analogous to tumor cells. Once both of these hits are activated, AD can develop and produce senile plaques and neurofibrillary tangles throughout brain tissue. In this review, we propose a mechanism for neuronal cell cycle reentry and the development of AD.

Fig. 23.1

Neurons subject to loss of connections or other stressors exit G₀ and reenter into the cell cycle that is abortive and leads to cell death

Fig. 23.2

Cell cycle reentry in a normal neuron leads only to death

Fig. 23.3

Cell cycle reentry in AD leads to a host of downstream sequelae including oxidative stress and death