Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency

Mutations in the homologous presenilin 1 (PS1) and presenilin 2 (PS2) genes cause the most common and aggressive form of familial Alzheimer's disease. Although PS1 function and dysfunction have been extensively studied, littl e is known about the function of PS2 in vivo. To delineate the relationship s of PS2 and PS1 activities and whether PS2 mutations involve gain or loss of function, we generated PSZ homozygous deficient (-/-) and PS1/PS2 double homozygous deficient mice. In contrast to PS1(-/-) mice, PS2(-/-) mice are viable and fertile and develop only mild pulmonary fibrosis and hemorrhage with age. Absence of PS2 does not detectably alter processing of amyloid p recursor protein and has little or no effect on physiologically important a poptotic processes, indicating that Alzheimer's disease-causing mutations i n PS2, as in PS1, result in gain of function. Although PS1(+/-) PS2(-/-) mi ce survive in relatively good health, complete deletion of both PS2 and PS1 genes causes a phenotype closely resembling full Notch-1 deficiency, These results demonstrate in vivo that PS1 and PS2 have partially overlapping fu nctions and that PS1 is essential and PS2 is redundant for normal Notch sig naling during mammalian embryological development.