MUTANT HUMAN PRESENILIN-1 PROTECTS PRESENILIN-1 NULL MOUSE AGAINST EMBRYONIC LETHALITY AND ELEVATES A-BETA-1-42 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 embryo nic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type huma n PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indica ting that the mutation does not lead to loss of PS1 function during de velopment. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mi ce does not lead to A beta 1-42/43 increase, whereas expression of hum an 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.