Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression

Mutations in presenilin I (PSI) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster production of A beta 1-42/43 in FAD patients and transgenic mice. PSI null mice are embryonic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type human PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indicating that the mutation does not lead to loss of PS1 function during development. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mice does not lead to A beta 1-42/43 increase, whereas expression of human mutant PS1 on murine PSI null background is sufficient to elevate A beta 1-42/43, supporting a gain-of-function activity as the result of the PS1 mutation.