A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Abstract

Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-β. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical α-, β-, and γ-secretases is simplistic, with the discovery of a number of novel APP secretases (including δ- and η-secretases, alternative β-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.

Keywords: ADAM; ADAM10; Alzheimer disease; amyloid; amyloid precursor protein (APP); amyloid-beta (AB); beta-secretase 1 (BACE1); cathepsin B (CTSB); presenilin; protease; proteolysis; secretase.

FIGURE 1.

The proteolytic processing of APP. A, the traditional model of APP proteolysis involves APP processing either in the non-amyloidogenic pathway, where sequential cleavage by α-secretase (ADAM10; pink) and the γ-secretase multisubunit complex (here shown for simplicity as a single entity; blue) liberates sAPPα and p3, or in the amyloidogenic pathway, where sequential cleavage by β-secretase (BACE1 or possibly cathepsin B; green) and γ-secretase liberates sAPPβ and Aβ. Both pathways produce AICD, which can be proteolytically degraded or translocated to the nucleus, where it has roles in transcriptional regulation. B, APP processing by the δ-secretase (AEP; yellow) causes the release of three soluble fragments of APP (sAPP_1–585, sAPP_1–373, and sAPP_374–585). The remaining CTFδ is then further processed by β- and γ-secretases to release Aβ and AICD. C, η-secretase (suggested to be MT5-MMP; orange) releases the soluble sAPPη fragment and leaves the membrane-bound CTFη. CTFη can be further processed by α- or β-secretase to release Aη-α or Aη-β, respectively. Following α- or β-cleavage, the remaining CTF can be cleaved by γ-secretase to release p3 and AICD, or Aβ and AICD, respectively. sec, secretase. D, meprin β (purple) acts as a β-secretase producing a fragment similar to sAPPβ as well as two shorter, soluble fragments (sAPP_1–380/3 and sAPP_1–124). The remaining CTF can then be processed by γ-secretase to release Aβ_2-X and AICD. See text for further details.

FIGURE 2.

Formation of Aβ by γ-secretase cleavage of APP CTFβ. Cleavage of APP CTFβ by γ-secretase follows a “nibbling” pattern in the direction indicated by the black arrows, where the initial (ϵ) cleavage dictates the final (γ) cleavage. The initial cleavage dictates the C-terminal length of Aβ and thus its amyloidogenic potential. N, N terminus; C, C terminus.