P1‐165: Evidence to Support γ‐Secretase Modulators: Short Aβ Peptides are Protective in Vivo

Background:An attractive therapeutic strategy to treat Alzheimer’s Disease is to halt the accumulation of amyloid plaques by decreasing the production of Ab1-42. A class of compounds called g-secretase modulators (GSMs) shift the g-secretase cleavage site of amyloid precursor protein resulting in a selective decreased production of amyloid beta (Ab) peptide 1-42 and a concomitant increased production of the shorter Ab peptides, Ab1-37, Ab1-38 and Ab1-39. However, the biological significance of these peptides is still unclear. Our initial studies with transgenic mouse models suggest that one such short peptide, Ab1-40, is a robust inhibitor of Ab1-42 deposition in vivo. The last two hydrophobic residues at the C-terminal of Ab1-42 are proposed to be critical for its enhanced rate of nucleation. Therefore we hypothesize that shorter Ab peptides are anti-amyloidogenic and modify the toxicity of Ab42 in vivo. Methods: In this study we examined the effect of Ab38, expressed using our BRI2 fusion strategy, in an APP mouse model and investigated the role of shorter Ab peptides, Ab1-36, Ab1-37, Ab1-38, Ab1-39, Ab1-40, Ab1-42 and Ab1-43, by generating transgenic Drosophila melanogaster. The Ab peptides were expressed independently or co-expressed with Ab1-42 specifically in the eye to assess phenotype and the neurons to evaluate behavioral function. Results: Overexpression of the shorter Ab peptides, Ab1-36, Ab1-37, Ab1-38 and Ab1-39, was not toxic in the eye. Overexpression of Ab1-42 resulted in a degenerative eye phenotype while expression of Ab1-40 or Ab1-43 had a slight effect on eye phenotype. Importantly, in flies co-expressing Ab1-42 and the shorter Ab peptides, Ab1-36, Ab1-37, Ab1-38 and Ab1-39, the degenerative phenotype and behavioral function was improved. Conclusions: These studies validate g-secretase modulation as a clinical strategy by characterizing the attenuating effect of shorter Ab peptides.