Implications of presenilin 1 mutations in Alzheimer's disease

Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are the most common genetic factors underlying the development of early-onset familial Alzheimer's disease (FAD). To investigate the pathogenic mechanism of PS1 mutations linked to FAD, we established inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1(M146L or Δexon 10) under the control of the Lac repressor. Using this inducible PS1 system, the influence of PS1 mutations on the generation of endogenous murine Aft species was assessed using a highly sensitive immunoblotting technique. The induction of mutated PS1 resulted in an increase in the extra- and intracellular levels of two distinct Aβ species ending at residue 42, Aβ1- 42 and its N-terminally truncated variant(s), Aβx-42. In addition, the intracellular generation of these Aβ42 species was completely blocked by brefeldin A. In contrast, it exhibited differential sensitivities to monensin such that there was an increased accumulation of intracellular Aβx-42 but an inhibition of intracellular Aβ1-42 generation. These data strongly suggest that Aβx-42 is generated in a proximal Golgi compartment, whereas Aβ1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific γ-secretase cleavage which occurs (i) in the ER or the early Golgi apparatus prior to γ-secretase cleavage, or (ii) in the distinct sites where Aβx-42 and Aβ1-42 are generated. To date, the site of Aβ42 generation has not been firmly established. Our data provide new information regarding the site of Aβ42 generation mediated by the FAD-linked mutant PS1.