P4-196: Presenilin in neuronal survival and neurodegeneration

Abstract

Background: Presenilins (PS) have been shown to exhibit -secretase dependent and independent activities, the former requires the D257 site and the latter is mediated through the hydrophilic loop domain encoded by exon 10. Mutations in presenilin genes (PS1 and PS2) lead to early-onset of Alzheimer’s disease (AD), and increasing evidence indicates that these mutations lead to a partial loss of function for its physiological activities. Methods: We are using PS conditional double knockout (PScDKO) mice in which both presenilin genes are postnatally deleted in the forebrain to gain insight into the pathophysiology of AD. We are investigating the -secretase dependent and independent functions in adult CNS by genetic rescue using mice containing the PS1D257A mutation or exon 10 loop deletion (PS1 E10), respectively. The in vivo analysis was complemented by primary neuronal culture studies. We examined neuronal cell cycle markers using immunohistochemical methods. Results: The PScDKO mice are viable and exhibit age-related neurodegenerative phenotypes. Cyclin D1 activation and neuronal cell cycle re-entry is one of the earliest hallmarks seen in PScDKO animals and in PS1 null neurons, and this is largely mediated through the PS1 loop domain. However, neurons marked with BrdU do not directly succumb to apoptosis, and -secretase defective mutant PS1D257A leads to neuronal cell death independent of cell cycle re-entry. Nevertheless, cell cycle abnormality enhances the neuronal vulnerability under stress conditions, and our data reveal p53 as a downstream effecter. Conclusions: The results support a model whereby the PS -secretase activity, in a cell cycle independent manner, plays a predominant role in neuronal homeostasis. The PS1 loop domain, through cyclin D1 and p53-dependent mechanisms, facilitates PS1 neuronal function, particularly under stress conditions.