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.

Keywords: Alzheimer's disease; Amyloid-beta; Gamma-secretase.

Fig. 1

Amyloid precursor protein (APP) can be cleaved in two major pathways. If it is first cleaved by alpha-secretase, then subsequent cleavage by gamma-secretase results in the intracellular domain (AICD) and p3, a non-amyloidogenic by-product. However, if beta-secretase performs the initial cleavage, then gamma-secretase cleaves the beta-CTF at multiple sites, sequentially releasing the AICD and Aβ peptides of varying lengths, which can oligomerize. The gamma-secretase cleavage sites are referred to as ε, ζ, and γ, and the starting amino acid, either 48 or 49, determines the end product, either Aβ338/42 or 37/40.

Fig. 2

Gamma-secretase is composed of four essential subunits: presenilin (PS1), Nicastrin (Nct), Pen-2, and APH-1. Presenilin must be endoproteolysed into the N and C terminal fragments to become active, and the catalytic residues (D*) are present in this subunit.

Fig. 3

Notch is crucial to maintaining neural progenitors. Notch inhibition maintains the progenitor pool for neurons, while Notch signaling drives glial progenitors to become astrocytes. By applying gamma-secretase inhibitors (GSIs) to induced pluripotent stem cells, researchers can drive progenitors into neurons.

Fig. 4

Gamma-secretase is vital to multiple neuronal processes. Through Notch signaling, GS is involved in the balance between neural stem cells (NSC) and neurons. GS also cleaves DCC, which regulates neurite outgrowth, neuroligin, which controls synaptic adhesion, and ephrin-B, which is involved in spine maturation.