Generation of Aβ38 and Aβ42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and γ-secretase modulation

Alzheimer disease amyloid β-peptide (Aβ) is generated via proteolytic processing of the β-amyloid precursor protein by β- and γ-secretase. γ-Secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Aβ(42) and concomitantly increase the levels of the rather benign Aβ(38). Here we show that Aβ(42) and Aβ(38) generation occur independently from each other. The amount of Aβ(42) produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of γ-secretase, appeared to correlate with the respective age of onset in patients. However, Aβ(38) levels did not show a negative correlation with the age of onset. Modulation of γ-secretase activity by sulindac sulfide reduced Aβ(42) in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Aβ(42) or only rather subtle effects. Strikingly, even the mutations that showed no effect on Aβ(42) levels allowed a robust increase of Aβ(38) upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Aβ(42) and to decrease Aβ(38). For mutants that predominantly produce Aβ(42), the ability of fenofibrate to further increase Aβ(42) levels became diminished, whereas Aβ(38) levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Aβ(38) and Aβ(42) production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Aβ(42)-lowering capacity of γ-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to γ-secretase modulators.