γ-secretase is a pleiotropic intramembrane-cleaving protease. It is a multiprotein complex that comprises presnilin
(PS), nicastrin (NCT), presnilin enhancer-2 (Pen-2), and anterior pharynx-defective-1 (Aph-1)—all of which are essential
for its proteolytic activity. Promiscuously diverse substrates are susceptible to cleavage by γ-secretase, of which
amyloid precursor protein (APP) and notch are the well-characterized substrates. Specifically, APP processing by γ -
secretase has garnered much attention, because the generation of amyloidogenic amyloid β peptide (Aβ) is the hallmark of
the pathogenesis of Alzheimer’s disease (AD). Thus, the regulatory mechanisms and substrate specificities of γ-secretase
proteolytic activity have been studied extensively as therapeutic targets of AD. Further, the processing of other substrates
has broad biological implications, releasing an intracellular domain that functions as a signaling molecule. Hence, γ -
secretase regulates many physiological functions and pathologies.
We summarize the current literatures on γ-secretase, including its assembly and substrates. Its diverse substrates and the
downstream events that are initiated by the release of the intracellular domains of substrates after γ-secretase cleavage are
discussed, as is their significance under normal and aberrant physiological conditions. Further, the regulation of γ -
secretase activity is broached to yield insights into using this promiscuous enzyme to develop therapeutic agents for AD.