The Cell Cycle Molecules Behind Neurodegeneration in Alzheimers Disease: Perspectives for Drug Development

A.      Copani; S.      Guccione; L.      Giurato; F.      Caraci; M.      Calafiore; M.   A.   Sortino; F.      Nicoletti

Abstract

Alzheimers disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are ß-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.

Keywords: Alzheimer's disease, β-amyloid, apoptosis, cell cycle, DNA replication, cyclin-dependent kinases, DNA polymerase-β, neuroprotection