Katarzyna Marta Zoltowska, et al. – VIB-KU Leuven, UC San Diego.
This study found that human Aβ42 reduces the activity of γ-secretase, leading to reduced cleavage of the APP C-terminal fragment as well as other γ-secretase targets such as Notch and p75. This effect is not observed with murine Aβ42 nor, in cell-based assays, other human Aβ products. This suggests that the molecular cascade linking Aβ42 to neurodegeneration involves inhibition of γ-secretase by Aβ42.
This study did not determine the relative contributions of impaired processing of APP versus other γ-secretase targets. However, a recent preprint studying C. elegans suggests a critical role for other targets, as impaired γ-secretase function triggered neurodegeneration in an animal lacking a version of APP that produces amyloid-β.
