Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

Abstract

Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (Aβ) by β-secretase and γ-secretase complex is at the heart of the pathogenesis of Alzheimer's disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of β- and γ-secretases as targets, new APP-cleaving enzymes, including meprin-β, legumain (δ-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/η-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology. This review will discuss recent findings on the roles of all these proteinases in the nervous system, and in particular on the roles of MT-MMPs, which are at the crossroads of pathological events involving not only amyloidogenesis, but also inflammation and synaptic dysfunctions. Assessing the potential of these emerging proteinases in the Alzheimer's field opens up new research prospects to improve our knowledge of fundamental mechanisms of the disease and help us establish new therapeutic strategies.

Keywords: amyloid precursor protein; caspase; eta-secretase; legumain; matrix metalloproteinases; meprin-beta; neurodegenerative disease; rhomboid-like protein-4.

FIGURE 1

Illustrative outline of the different APP cleavage sites. The scheme shows the canonical (β-, α- and γ-secretases) and non-canonical APP-cleavages that result in the different APP fragments. Meprin-β cleaves APP in five sites, possibly generating soluble APP fragments of different size, sAPPβ or sAPPβ-like (sAPPβ with one or two additional amino acids) and its complementary C-terminal β-CTF or β-CTF-like (β-CTF with one or two amino acids less), which is further processed by γ-secretase, thus producing Aβ_1–X, Aβ_2–X or Aβ_3–X. Legumain cleaves in two sites, giving rise to two soluble fragments and one C-terminal transmembrane fragment than can be further processed by the canonical enzymes. Caspase can cleave in the N-terminal domain, generating truncated APP-species, and within the intracytoplasmic domain, generating an APP-Ncas fragment and a C-terminal residual peptide of 31 amino acids. RHBDL4 cleavages within the ectodomain at several sites are not yet identified (represented with a star), generating different N- and C-terminal fragments. Cleavage by η-secretase generates a soluble fragment (sAPPη/sAPP95) and a paired transmembrane product η-CTF/CTF-30 that can be further processed by β- or α-secretase to release Aη-β and Aη-α, respectively. MT3-MMP can cleave APP in 4 sites, including the η-secretase site and also within the Aβ sequence. The scheme below represents the Aβ sequence with multiple cleavage sites for various soluble MMPs and MT1-MMP, for meprin-β and for canonical secretases. All the residues are termed using APP₆₉₅ numbering.