Alzheimer's disease (AD) is characterized by extensive loss of neurons, however, the mechanisms by which neurons die is presently unresolved. There is now accumulating evidence that many of the neurons die apoptotically through the unscheduled and abortive entry into the cell cycle. The expression of cell cycle regulatory proteins in post-mitotic neurons is paradoxical given the irreversible withdrawal of these cells from the cell cycle following the terminal division. Our previous studies have documented that neurons in the AD brain aberrantly express cell cycle proteins. These findings have led us to investigate the involvement of abortive cell cycle initiation in neuronal cell death in a tissue culture model and in tissue from the AD brain. There is compelling evidence supporting the involvement of inflammatory processes in the progression of AD. The senile plaque is the focus of a chronic local inflammatory response mediated by activated microglia which secrete a broad range of pro-inflammatory and neurotoxic products. The senile plaque is the focus of a chronic local inflammatory response mediated by activated microglia which secrete a broad range of pro-inflammatory and neurotoxic products. We have investigated the hypothesis that microglial secretory products provoke neuronal death by stimulating neurons to reenter the cell cycle. We have investigated the hypothesis that microglial secretory products provoke neuronal death by stimulating neurons to reenter the cell cycle. We have demonstrated that cortical neurons respond to microglial neurotoxins by induction of cyclin D1 and PCNA expression and the incorporation of BrdU into DNA. Importantly, we demonstrate that cells undergoing DNA synthesis die apoptotically.
The specific aims of this proposal are 1) to identify the neurotoxic factors elaborated by the microglia. 2) To investigate the expression and regulatory actions of G1 cell cycle regulators including cyclin D1, cdk4, the cdk inhibitors p16, p21 waf1 following exposure to the cells to microglial derived neurotoxins. We will perform a functional evaluation of cell cycle elements in the induction of neuronal apoptosis by ectopically expressing cyclin D1 and its specific inhibitor, 16ink4a and examination of neurons derived from animals in which the cyclin D1, p16ink4a and JNK3 genes have been inactivated. 4) Neurons are able to incorporate BrdU prior to their apoptotic death and we propose to determine if the incorporation of nucleoside analogs into DNA represents bonafide DNA replication by analyzing the nascent DNA replications by fluorescence in situ hybridization (FISH).
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