APH1 was initially identified as a component of the Notch pathway in C. elegans. Along with nicastrin, PEN2, and presenilin-1 APH1 is an essential component of the gamma-secretase complex which cleave the amyloid precursor protein (APP) at what are known as the gamma- and epsilon-sites and can lead to the accumulation of the Amyloid beta peptide (Abeta) cleavage product that is associated with Alzheimer’s disease. APH1 exists in at least three distinct isoforms with APH1a as the principal isoform present in the gamma-secretase complex. Mice deficient in this isoform, but not the other two, were lethal at E10.5, with impaired vascular and neural development observed. Despite its predicted molecular weight, APH1 protein often migrates at aberrant locations in SDS-PAGE.

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