Neurotoxic amyloid-β peptide (Aβ) 42/43 species generated by β-secretase and γ-secretase from the β-amyloid precursor protein (APP) are believed to trigger Alzheimer's disease (AD). Relative increases of these species due to mutations in APP and presenilin/γ-secretase are associated with the vast majority of early onset familial AD cases. Important breakthroughs have recently been made in elucidating the mechanism(s) of these mutations, showing that altered substrate interactions and substrate-enzyme complex stabilities are underlying their pathogenic Aβ generation. Moreover, first structures of γ-secretase in complex with APP and Notch1 substrates allow insight into how substrate cleavage could be initiated and further progress has been made in the mechanistic understanding of γ-secretase modulators, advanced Aβ-lowering drugs. These insights could be exploited for future AD clinical trials.
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