Aβ43‐producing PS1 FAD mutants cause altered substrate interactions and respond to γ‐secretase modulation

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.