Cell Cycle Activation and the Amyloid-β Protein in Alzheimer’s Disease

Morphological changes that characterize Alzheimer’s disease (AD) are senile plaques, neurofibrillary tangles, and loss of synapses and neurons. At the center of the senile plaque is the polypeptide amyloid-β (Aβ), a product of a transmembrane protein called Aβ protein precursor (AβPP). Aβ formation, deposition, and toxicity have been associated with the cell cycle. Indeed, the mitogenic component appears early in the onset of AD with the reappearance of cell cycle markers and recently has been associated with selective early vulnerability of neurons. Also, because Aβ is mitogenic in vitro, it can induce and maintain cell cycle events in AD. Aβ-mediated cell death in vitro is dependent on the presence of various cell cycle-related elements. Therefore the activation of cell cycle machinery in vivo in the neuron may also similarly mediate its toxic effects. For decades the predominant thinking was that adult neurons do not proliferate. This conclusion resulted from the observation that differentiated neurons fail to divide. In this chapter, it is hypothesized that, in AD, whole populations of non-stem-cell neurons leave their quiescent state and re-enter the cell cycle. However, such neuronal re-entry into the cell cycle is ineffective and eventually leads to neurodegeneration and ultimately AD. Not only AP but all of the major genetic and protein elements deregulated in AD are to some extent altered in the nonefficient cell cycle. This group of factors includes AβPP, τ, the presenilins (PSEN1 and PSEN2), and, possibly, apolipoprotein E (ApoE). In addition, AD-related proteins such as ApoE, free radicals, free-radical generators, and antioxidants function also to control the state of the cell cycle. Investigating more defined mechanisms of cell cycle-related activation and arrest in AD involving AP and other factors may provide clues to change the natural course of this illness.