Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications

Neurotoxic amyloid-beta peptide (Abeta) 42/43 species generated by beta-secretase and gamma-secretase from the beta-amyloid precursor protein (APP) are believed to trigger Alzheimer's disease (AD). Relative increases of these species due to mutations in APP and presenilin/gamma-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 Abeta generation. Moreover, first structures of gamma-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 gamma-secretase modulators, advanced Abeta-lowering drugs. These insights could be exploited for future AD clinical trials.