pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity.

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.