Recent studies have shown that various cell cycle proteins are expressed in post-mitotic neurons within affected brain regions during Alzheimer's disease (AD). Cell cycle proteins have been proposed to function in mechanisms of neuronal cell death during AD. To further explore the role of cell cycle proteins in neurodegeneration associated with AD, we utilized PC12 cells to examine the subcellular distribution of cell cycle transcriptional regulators, including the retinoblastoma gene product (pRb), E2F1 and FAC1, during beta-amyloid (Abeta)-induced neurodegeneration. Moreover, we examined the immunolocalization of pRb and E2F1 in non-demented control and AD brain tissue. We found that pRb exhibited increased levels of Ser795 phosphorylation in response to Abeta in the nucleus of PC12 cells and also in the nucleus of a subset of neurons during AD. E2F1 was distributed throughout the cytoplasm and neurites of PC12 cells in response to Abeta and in the cytoplasm of cells in AD brain. FAC1 exhibited a rapid redistribution from the cytoplasm to the perinuclear region in PC12 cells treated with Abeta. These data indicate that altered phosphorylation and subcellular distribution of transcriptional regulators occur in response to Abeta-induced neurotoxicity and during AD.