Growing evidence suggests that one of the earliest events in the neuronal degeneration of Alzheimer's disease (AD) is aberrant cell-cycle activation in postmitotic neurons, which may, in fact, be sufficient to initiate the neurodegenerative cascade. In the present study we examined whether cyclins and cyclin-dependent kinases, molecules normally associated with cell-cycle control, may be involved in delayed expression of altered Alzheimer's proteins in two interconnected areas, the entorhinal cortex (EC) and the dentate gyrus (DG), after a hippocampal excitotoxic lesion. Several cell-cycle proteins of the G1 and S phases and even of the G2 phase were found to be up-regulated in the EC after kainic acid evoked neuronal death in the hippocampus. In addition, we describe the progressive expression of two Alzheimer's-related proteins, PHF-1 and APP, which reached higher levels immediately after the increase in G1/S-phase markers. Hence, the results of the present study support the participation of cell-cycle dysregulation as a key component of the process that may ultimately lead to expression of AD proteins and neuronal death in a brain area when the target site for synaptic inputs in that area is damaged by an excitotoxic insult. © 2007 Wiley-Liss, Inc.