Assembly, Maturation, and Trafficking of the γ-Secretase Complex in Alzheimers Disease

Abstract

In this review, we discuss the biology of gamma-secretase, an enigmatic enzyme complex that is responsible for the generation of the amyloid-beta peptide that constitutes the amyloid plaques of Alzheimer's disease. We begin with a brief review on the processing of the amyloid precursor protein and a brief discussion on the family of enzymes involved in regulated intramembrane proteolysis, of which gamma-secretase is a member. We then identify the four major components of the gamma-secretase complex - presenilin, nicastrin, Aph-1, and Pen-2 - with a focus on the identification of each and the role that each plays in the maturation and activity of the complex. We also discuss two new proteins that may play a role in modulating the assembly and activity of the gamma-secretase complex. Next, we summarize the known subcellular locations of each gamma-secretase component and the sites of gamma-secretase activity, as defined by the production of Abeta. Finally, we close by synthesizing all of the included topics into an overarching model for the assembly and trafficking of the gamma-secretase complex, which serves as a launching point for further questions into the biology and function of gamma-secretase in Alzheimer's disease.

Trafficking and Proteolytic Processing of APP

“…This apparent contradiction was coined the spatial paradox by Annaert and De Strooper (1999). Although still not resolved completely, the work of many labs now indicates that mature, proteolytically active PS/g-secretase is principally localized not in ER, Golgi, or postGolgi transport vesicles but rather at the PM and in the endosomal/lysosomal system, including phagosomes and autophagosomes (reviewed in Pasternak et al 2004;Kaether et al 2006a;Nixon 2007;Dries and Yu 2008). The g-secretase subunits found in the ER/early secretory pathway most likely represent unassembled or partially assembled subcomplexes, but not the active enzyme.…”

Presenilin Transmembrane Domain 8 Conserved AXXXAXXXG Motifs Are Required for the Activity of the γ-Secretase Complex

“…In mammals, there are two homologous presenilins (PS1 and PS2). The assembly of the ␥-secretase complex requires the association of either PS1 or PS2 with three other membrane proteins: nicastrin (NCT), anterior pharynx defective 1 (APH-1a or APH-1b), and presenilin enhancer 2 (PEN-2) (13,14). Presenilins have nine transmembrane domains (TMDs) (15), and the two catalytic aspartic acid residues are located on its TMD6 and -7, both required for substrate hydrolysis.…”

Lack of Evidence for Presenilins as Endoplasmic Reticulum Ca2+ Leak Channels

“…Alzheimer disease (AD) 3 is the most common cause of dementia among individuals over 60 years old, affecting ϳ2% of people in industrialized countries. Although most AD is idiopathic with late onset (Ͼ60 years of age), a small percentage of AD is characterized by early onset and dominant-negative inheritance.…”

“…Aspartic acid at position 257 is required for intramolecular cleavage of PS1 into mature fragments. Mutation of this residue causes the accumulation of PS holoprotein in the ER (3,39) (Fig. 3A).…”