title: Physiological and pathological roles of the γ-secretase complex.
abstract: Gamma-secretase (GS) is an enzyme complex that cleaves numerous substrates, and it is best known for cleaving amyloid precursor protein (APP) to form amyloid-beta (Aβ) peptides. Aberrant cleavage of APP can lead to Alzheimer's disease, so much research has been done to better understand GS structure and function in hopes of developing therapeutics for Alzheimer's. Therefore, most of the attention in this field has been focused on developing modulators that reduce pathogenic forms of Aβ while leaving Notch and other GS substrates intact, but GS provides multiple avenues of modulation that could improve AD pathology. GS has complex regulation, through its essential subunits and other associated proteins, providing other targets for AD drugs. Therapeutics can also alter GS trafficking and thereby improve cognition, or move beyond Aβ entirely, effecting Notch and neural stem cells. GS also cleaves substrates that affect synaptic morphology and function, presenting another window by which GS modulation could improve AD pathology. Taken together, GS presents a unique cross road for neural processes and an ideal target for AD therapeutics.
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, NY, United States; Program of Neuroscience, Weill Graduate School of Medical Sciences of Cornell University, NY, United States. Electronic address: cmc2018@med.cornell.edu.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Carroll
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, NY, United States; Program of Neuroscience, Weill Graduate School of Medical Sciences of Cornell University, NY, United States; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, NY, United States.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D006801:Humans; D058953:Neural Stem Cells / Q000201:enzymology; D009474:Neurons / Q000201:enzymology
chemical_list: D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Amyloid-beta; Gamma-secretase