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The Journal of Neuroscience, October 29, 2008, 28(44):11421-11431; doi:10.1523/JNEUROSCI.2873-08.2008

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Neurobiology of Disease
Genetic Dissection of -Secretase-Dependent and-Independent Functions of Presenilin in Regulating Neuronal Cell Cycle and Cell Death

Verena Kallhoff-Munoz,^1,2 Lingyun Hu,³ Xiaoli Chen,² Robia G. Pautler,³ and Hui Zheng^1,2

¹Department of Molecular and Human Genetics, ²Huffington Center on Aging, and ³Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: huiz{at}bcm.edu

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 -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 -secretase-dependent and -independent activities of PS in the adult CNS. Whereas -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 -secretase activity is essential in maintaining neuronal viability, and the PS1 loop domain modulates neuronal homeostasis through cell cycle and cytoplasmic p53 control.

Key words: Alzheimer's disease; presenilin; -secretase; neurodegeneration; cell cycle events; mice

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Received June 23, 2008; accepted Sept. 24, 2008.

Correspondence should be addressed to Hui Zheng, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: huiz{at}bcm.edu

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