Cell cycle markers have been shown to be upregulated and proposed to lead to apoptosis of postmitotic neurons in Alzheimer's disease (AD). Presenilin (PS) plays a critical role in AD pathogenesis, and loss-of-function studies in mice established a potent effect of PS in cell proliferation in peripheral tissues. Whether PS has a similar activity in the neuronal cell cycle has not been investigated. PS exhibits gamma-secretase-dependent and -independent functions; the former requires aspartate 257 (D257) as part of the active site, and the latter involves the hydrophilic loop domain encoded by exon 10. We used two novel mouse models, one expressing the PS1 D257A mutation on a postnatal PS conditional knock-out background and the other deleting exon 10 of PS1, to dissect the gamma-secretase-dependent and -independent activities of PS in the adult CNS. Whereas gamma-secretase plays a dominant role in neuronal survival, our studies reveal potent neuronal cell cycle regulation mediated by the PS1 hydrophilic loop. Although neurons expressing cell cycle markers do not directly succumb to apoptosis, they are more vulnerable under stress conditions. Importantly, our data identify a novel pool of cytoplasmic p53 as a downstream mediator of this cellular vulnerability. These results support a model whereby the PS gamma-secretase activity is essential in maintaining neuronal viability, and the PS1 loop domain modulates neuronal homeostasis through cell cycle and cytoplasmic p53 control.