Processing of amyloid-β (Aβ) precursor protein (APP) by γ-secretase produces multiple species of Aβ: Aβ40, short Aβ peptides (Aβ37–39), and longer Aβ peptides (Aβ42–43). γ-Secretase modulators, a class of Alzheimer’s disease therapeutics, reduce production of the pathogenic Aβ42 but increase the relative abundance of short Aβ peptides. To evaluate the pathological relevance of these peptides, we expressed Aβ36–40 and Aβ42–43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on Aβ42 toxicity. In contrast to Aβ42, the short Aβ peptides were not toxic and, when coexpressed with Aβ42, were protective in a dose-dependent fashion. In parallel, we explored the effects of recombinant adeno-associated virus–mediated expression of Aβ38 and Aβ40 in mice. When expressed in nontransgenic mice at levels sufficient to drive Aβ42 deposition, Aβ38 and Aβ40 did not deposit or cause behavioral alterations. These studies indicate that treatments that lower Aβ42 by raising the levels of short Aβ peptides could attenuate the toxic effects of Aβ42.

γ-分泌酶对淀粉样蛋白-β (Aβ) 前体蛋白 (APP) 的加工产生多种 Aβ：Aβ40、短 Aβ 肽 (Aβ37-39) 和较长的 Aβ 肽 (Aβ42-43)。γ-分泌酶调节剂是一类阿尔茨海默病治疗剂，可减少致病性 Aβ42 的产生，但增加短 Aβ 肽的相对丰度。为了评估这些肽的病理相关性，我们在黑腹果蝇中表达了 Aβ36-40 和 Aβ42-43评估固有毒性和对 Aβ42 毒性的潜在调节作用。与 Aβ42 相比，短 Aβ 肽没有毒性，并且当与 Aβ42 共表达时，具有剂量依赖性的保护作用。同时，我们探讨了重组腺相关病毒介导的 Aβ38 和 Aβ40 在小鼠中表达的影响。当在非转基因小鼠中以足以驱动 Aβ42 沉积的水平表达时，Aβ38 和 Aβ40 不会沉积或导致行为改变。这些研究表明，通过提高短 Aβ 肽水平来降低 Aβ42 的治疗可以减轻 Aβ42 的毒性作用。