Interaction of Alzheimer's presenilin-1 and presenilin-2 with Bcl-X-L - A potential role in modulating the threshold of cell death

The familial Alzheimer's disease gene products, presenilin-1 and presenilin -2, have been reported to be functionally involved in amyloid precursor pro tein processing, notch receptor signaling, and programmed cell death or apo ptosis. However, the molecular mechanisms by which presenilins regulate the se processes remain unknown. With regard to the latter, we describe a molec ular link between presenilins and the apoptotic pathway. Bcl-X-L, an anti-a poptotic member of the Bcl-2 family was shown to interact with the carboxyl -terminal fragments of PS1 and PS2 by the yeast two-hybrid system. In vivo interaction analysis revealed that both PS2 and its naturally occurring car boxyl-terminal products, PS2short and PS2Ccas, associated with Bcl-X-L, whe reas the caspase-3-generated amino-terminal PS2Ncas fragment did not. This interaction was corroborated by demonstrating that Bcl-X-L and PS2 partiall y co-localized to sites of the vesicular transport system. Functional analy sis revealed that presenilins can influence mitochondrial-dependent apoptot ic activities, such as cytochrome c release and Bar-mediated apoptosis. Tog ether, these data support a possible role of the Alzheimer's presenilins in modulating the anti-apoptotic effects of Bcl-X-L.