AβPP processing results in greater toxicity per amount of Aβ1-42 than individually expressed and secreted Aβ1-42 in Drosophila melanogaster.

摘要: The aggregation of the amyloid-β (Aβ) peptide into fibrillar deposits has long been considered key neuropathological hallmark Alzheimer's disease (AD). Aβ peptides are generated from proteolytic processing transmembrane precursor protein (AβPP) via sequential proteolysis through β-secretase activity β-site AβPP-cleaving enzyme (BACE1) and by intramembranous γ-secretase. For over a decade, Drosophila melanogaster used as model organism to study AD, two different approaches have developed investigate toxicity caused AD-associated gene products in vivo In one model, is directly over-expressed fused signal peptide, allowing secretion extracellular space. other human AβPP co-expressed with BACE1, resulting production BACE1 endogenous fly Here, we performed parallel flies that expressed Aβ1-42 alone or BACE1. Toxic effects (assessed eye phenotype, longevity locomotor assays) levels Aβ1-42, Aβ1-40 Aβ1-38 were examined. Our data reveal toxic effect per amount detected was higher co-expressing than Aβ1-42-expressing flies, co-existence could be significant importance neurotoxic these flies. Thus, models seems modes action highly dependent on how where rather actual level This important knowledge needs taken consideration when using mechanisms therapeutic strategies AD research.