Physiological and pathological roles of the γ-secretase complex

• The subunit composition and structure of gamma-secretase.
• How the enzyme complex is regulated and trafficked.
• The role of gamma-secretase in neural stem cells.
• The contribution of non-canonical gamma-secretase substrates to neural processes.

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.