The γ-secretase enzyme (EC 3.4.23.46) is a multi-subunit enzyme complex that consists of four core components (presenilin, nicastrin, APH-1, and PEN-2). Presenilin is an aspartic protease and the catalytic component of the complex. γ-Secretase has the unusual ability to regulate intramembrane proteolysis (RIP) for a growing list of type 1 integral membrane proteins, including, APP, APP-like proteins (APLPs), E-Cadherin, ErbB4, ephrinB2, CD44, lipoprotein receptor-related protein (LRP), Notch, sterol regulatory element-binding protein (SREBP), interferon response element (IRE1), and activated transcription factor 6 (ATF-6). Especially for its capability to hydrolyze APP into amyloid-beta (Aβ) peptide whose abnormally folded fibrillar form is the primary component of amyloid plaques, γ-secretase is a well-known pharmacological target in the field of Alzheimer’s disease.