Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase

Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and γ-secretase to release amyloid peptides (Aβ40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Aβ40/42 is generated by γ-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Aβ40 : 42 to favor Aβ42. One hypothesis to explain this outcome is that mutant PS alters the specificity of γ-secretase to favor production of Aβ42 at the expense of Aβ40. To test this hypothesis in vivo, we studied Aβ40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Aβ42 and the rate of amyloid deposition. We further show that the shift in Aβ42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Aβ42, while maintaining a constant level of Aβ40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of γ-secretase and its access to substrates.