Ass40 Displays Amyloidogenic Properties In The Non-Transgenic Mouse Brain But Does Not Exacerbate Ass42 Toxicity Indrosophila

Background Self-assembly of the amyloid-beta (A beta) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer's disease (AD). However, it is clear that not all forms of A beta are equally harmful and that linking a specific aggregate to toxicity also depends on the assays and model systems used (Haass et al., J Biol. Chem 269:17741-17748, 1994; Borchelt et al., Neuron 17:1005-1013, 1996). Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between A beta deposition and neurodegeneration. Methods In this study, we examined familial mutations of A beta that increase aggregation and oligomerization, E22G and Delta E22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-A beta fusion technology and rAAV2/1-based somatic brain transgenesis in mice to selectively express individual mutant A beta species in vivo. In parallel, we generated PhiC31-based transgenicDrosophila melanogasterexpressing wild-type (WT) and A beta 40 and A beta 42 mutants, fused to the Argos signal peptide to assess the extent of A beta 42-induced toxicity as well as to interrogate the combined effect of different A beta 40 and A beta 42 species. Results When expressed in the mouse brain for 6 months, A beta 42 E22G, A beta 42 E22Q/D23N, and A beta 42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while A beta 40WT showed no distinctive phenotype, A beta 40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant A beta 40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant A beta 42 E22G, E22Q, and S26C, but not A beta 40, were toxic to the eye ofDrosophila. In contrast, flies expressing a copy of A beta 40 (WT or mutants), in addition to A beta 42WT, showed improved phenotypes, suggesting possible protective qualities for A beta 40. Conclusions These studies suggest that while some A beta 40 mutants form unique amyloid aggregates in mouse brains, they do not exacerbate A beta 42 toxicity inDrosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.