Abnormal generation of neurotoxic amyloid-β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 (PS1) subunit of γ-secretase is the major cause of familial Alzheimer's disease (FAD). Deeper mechanistic insight on the generation of Aβ43 is still lacking, and it is unclear whether γ-secretase modulators (GSMs) can reduce the levels of this Aβ species. By comparing several types of Aβ43-generating FAD mutants, we observe that very high levels of Aβ43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of Aβ, are found for all mutants and are independent of their particular effect on Aβ production. Furthermore, unlike previously described GSMs, the novel compound RO7019009 can effectively lower Aβ43 production of all mutants. Finally, substrate-binding competition experiments suggest that RO7019009 acts mechanistically after initial C99 binding. We conclude that altered C99 interactions are a common feature of diverse types of PS1 FAD mutants and that also patients with Aβ43-generating FAD mutations could in principle be treated by GSMs.

中文翻译：

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产生 Aβ43 的 PS1 FAD 突变体会​​导致底物相互作用改变并对 γ 分泌酶调节做出反应。


由于 γ-分泌酶的催化早老素 1 (PS1) 亚基突变导致神经毒性淀粉样蛋白 - β 肽 (Aβ) 42/43 种类的异常生成，是家族性阿尔茨海默病 (FAD) 的主要原因。目前仍缺乏对 Aβ43 生成的更深入的机制了解，并且尚不清楚 γ-分泌酶调节剂 (GSM) 是否可以降低这种 Aβ 物质的水平。通过比较几种类型的产生 Aβ43 的 FAD 突变体，我们观察到当早老素功能严重受损时，通常会产生非常高水平的 Aβ43。所有突变体中都发现了 Aβ 前体 C99 相互作用的改变，并且与其对 Aβ 产生的特定影响无关。此外，与之前描述的 GSM 不同，新型化合物 RO7019009 可以有效降低所有突变体的 Aβ43 产量。最后，底物结合竞争实验表明 RO7019009 在初始 C99 结合后发挥作用。我们得出的结论是，C99 相互作用的改变是不同类型 PS1 FAD 突变体的共同特征，并且原则上具有 Aβ43 生成 FAD 突变的患者也可以通过 GSM 进行治疗。