Implications of presenilin 1 mutations in Alzheimer's disease

Mutations in presenilin 1 (PSI) and presenilin 2 (PS2) are the most common genetic factors underlying the development of early-onset familial Alzheime r's disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cel l lines expressing the human wild type (wt) or mutated PS1(M146L or Delta e xon 10) under the control of the Lac repressor. Using this inducible PSI sy stem, the influence of PSI mutations on the generation of endogenous murine A beta species was assessed using a highly sensitive immunoblotting techni que. The induction of mutated PSI resulted in an increase in the extra- and intracellular levels of two distinct A beta species ending at residue 42, A beta 1-42 and its N-terminally truncated variant(s), A beta x-42. In addi tion, the intracellular generation of these A beta 42 species was completel y blocked by brefeldin A. In contrast, it exhibited differential sensitivit ies to monensin such that there was an increased accumulation of intracellu lar A beta x-42 but an inhibition of intracellular A beta 1-32 generation. These data strongly suggest that A beta x-42 is generated in a proximal Gol gi compartment, whereas A beta 1-12 is generated in a distal Golgi and/or a post-Golgi compartment. Thus. it appears that PSI mutations enhance the de gree of 42-specific gamma-secretase cleavage which occurs ii) in the ER or the early Golgi apparatus prior to gamma-secretase cleavage, or (ii) in the distinct sites where A beta x-42 and A beta 1-32 are generated. To date, t he site of A beta 42 generation has not been firmly established. Our data p rovide new information regarding the site of A beta 42 generation mediated by the FAD-linked mutant PS1. (C) 1999 Elsevier Science Ireland Ltd. All ri ghts reserved.