biostudies-literatureUnknown71(13)Han JThe gamma (γ)-secretase holoenzyme is composed of four core proteins and cleaves APP to generate amyloid beta (Aβ), a key molecule that causes major neurotoxicity during the early stage of Alzheimer's disease (AD). However, despite its important role in Aβ production, little is known about the regulation of γ-secretase. OCIAD2, a novel modulator of γ-secretase that stimulates Aβ production, and which was isolated from a genome-wide functional screen using cell-based assays and a cDNA library comprising 6,178 genes. Ectopic expression of OCIAD2 enhanced Aβ production, while reduction of OCIAD2 expression suppressed it. OCIAD2 expression facilitated the formation of an active γ-secretase complex and enhanced subcellular localization of the enzyme components to lipid rafts. OCIAD2 interacted Cellular and molecular life sciences : CMLS2561-76https://www.ebi.ac.uk/biostudies/studies/S-EPMC11113593biostudies-literatureOCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin.PMC11113593Choi HNah JNishimura MKam TIHan JJang JJo DGNakagawa TKim BJJung SJung YKfalseOCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin.The gamma (γ)-secretase holoenzyme is composed of four core proteins and cleaves APP to generate amyloid beta (Aβ), a key molecule that causes major neurotoxicity during the early stage of Alzheimer's disease (AD). However, despite its important role in Aβ production, little is known about the regulation of γ-secretase. OCIAD2, a novel modulator of γ-secretase that stimulates Aβ production, and which was isolated from a genome-wide functional screen using cell-based assays and a cDNA library comprising 6,178 genes. Ectopic expression of OCIAD2 enhanced Aβ production, while reduction of OCIAD2 expression suppressed it. OCIAD2 expression facilitated the formation of an active γ-secretase complex and enhanced subcellular localization of the enzyme components to lipid rafts. OCIAD2 interacted 2014-01-01T00:00:00Z2014 Jul2026-04-12T19:23:54.296Z2026-04-07T13:17:23.907ZS-EPMC111135932427085510.1007/s00018-013-1515-x