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Several species of β-amyloid peptides (Aβ) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aβ peptides. Several N-terminal modified Aβ peptides have also been identified in Alzheimer’s disease (AD) brains, the most common of which is pyroglutamate-modified Aβ (Aβ pE3-42 ). Aβ pE3-42  peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ 1-42  deposition. Moreover, in vitro studies have shown that Aβ pE3-42  can act as a seed for full length Aβ 1-42.  In this study, we characterized the  Drosophila  model of Aβ pE3-42  toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that Aβ pE3-42  peptide had an increased propensity to aggregate. Expression of Aβ pE3-42  in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of Aβ pE3-42  constitutively in the eyes led to disorganised ommatidia, and activation of the c-Jun N-terminal kinase (JNK) signaling pathway. The eye disruption was almost completely rescued by co-expressing a candidate Aβ degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading Aβ pE3-42.  Also, we tested the seeding hypothesis for Aβ pE3-42  in vivo, and measured its effect on Aβ 1-42  levels. We found that Aβ 1-42  levels were significantly increased when Aβ 1-42  and Aβ pE3-42  peptides were co-expressed. Furthermore, we found that Aβ pE3-42  enhanced Aβ 1-42  toxicity in vivo. Our findings implicate Aβ pE3-42  as an important source of toxicity in AD, and suggest that its specific degradation could be therapeutic.   Electronic supplementary material  The online version of this article (doi:10.1186/s40478-016-0380-x) contains supplementary material, which is available to authorized users.

pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity