Altered distribution of cell cycle transcriptional regulators during Alzheimer disease

A number of mechanisms have been proposed to contribute to the selective neuronal cell loss observed during Alzheimer disease (AD). These include the formation and accumulation of amyloid-beta (Abeta)-containing plaques, neurofibrillary tangles (NFTs), and inflammatory processes mediated by astrocytes and microglia. Neuronal responses to such insults in AD brain include increased protein levels and immunoreactivity for kinases known to regulate cell cycle progression. One down-stream target of these cell cycle regulatory proteins, the Retinoblastoma susceptibility gene product (pRb), has been shown to exhibit altered expression patterns in AD. Furthermore, in vitro studies have implicated pRb and one of the transcription factors it regulates, E2F1, in Abeta-induced cell death. To further explore the role of these proteins in AD, we examined the distribution of the E2F1 transcription factor and the hyperphosphorylated form of pRb (ppRb), which is unable to bind and regulate E2F activity, in the cortex of patients with AD and in non-demented controls. We observed increased ppRb and E2FI immunoreactivity in AD brain, with ppRb predominately located in the nucleus and E2F1 in the cytoplasm. Although neither of these proteins significantly co-localized with NFTs, both ppRb and E2F1 were found in cells surrounding a subset of Abeta-containing plaques. These results support a role for G1 to S phase cell cycle regulators in AD.