In vivo investigations of presenilin 1: from development to pathology

Abstract

Mutations in the presenilin 1 (PS1) gene are responsible for most cases of familial Alzheimer's disease. Although the biological functions of PS1 are not yet fully understood, it appears that the protein plays a role in the processing/trafficking of proteins such as Notch 1, Ire 1 and the amyloid precursor protein. The fact that PS1 knockout mice are not viable and have obvious developmental abnormalities has raised the possibility that the protein has an important role in development and programmed cell death. To investigate a possible role for PS1 in programmed cell death during development, we have studied the expression of this protein in the mammalian retina. During the course of retinal development, there were consistent changes in the distribution of PS1 immunoreactive cells evident at times when processes of lamination and differentiation were under way. There was little correlation between the changes in PS1 expression and the appearance of cells undergoing apoptotic cell death, as visualized using the TUNEL technique. This would suggest that the protein does not play a major role in developmental programmed cell death. In addition, using Western blot analysis, we detected a change in the pattern of PS1 proteolytic fragments, suggestive of an alternative cleavage site in the PS1 molecule that is developmentally regulated. Previous work performed in our laboratory showed that injection of aggregated Aβ into the vitreous body of the rat eye induces apoptotic cell death of specific neuronal populations of the retina. Interestingly, cells that normally express PS1, in the ganglion cell layer, were spared. Using Western blot analysis, we detected an increase in a fragment of PS1 in eyes injected with Aβ. This raises the possibility that, far from being pro-apoptotic, PS1 acts as a stress response protein and this may account for the resistance of ganglion cells to Aβ neurotoxicity.