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.

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

“…Aβ peptides derive from the proteolytic processing of the amyloid precursor protein (APP) by proteases called βand γ-secretase [4][5][6]. In addition to the generation and deposition of wellcharacterized Aβ40 and Aβ42 amino acid length variants, recent studies also showed the occurrence of several Nand C-terminally truncated or elongated Aβ species that result from alterations in the cleavage by βand γ-secretase or alternative processing by other proteases [7][8][9][10][11][12][13]. Additional heterogeneity in Aβ peptides comes from a number of post-translational modifications that are also found in characteristic Aβ deposits in parenchymal extracellular plaques and cerebral amyloid angiopathy (CAA) [14][15][16][17][18][19][20][21][22].…”

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

“…Although we cannot exclude that other recently discovered APP-processing enzymes (e.g., meprin β, δ-secretase [1,39,2] might cooperate with MT5-MMP, this is rather unlikely because HEK cells do not constitutively express meprin β, and even when overexpressed, this metalloproteinase does not release sAPP95 [40,41]. Moreover, TIMPs do not inhibit meprins [42], while TIMP-2 efficiently blocked the generation of sAPP95 by MT5-MMP.…”

“…The accumulation of C99 and C83 after deletion of the IC domain of MT1-MMP was the inverse of the effect caused by the deletion of the IC domain of MT5-MMP, strongly suggesting specific effects of the two homologue proteinases. Although they share 55.6% sequence identity, in the short IC domain of 20 amino acids the homology falls to only 20% [2], which might explain their specificities of action. In this context, only the active MT1-MMP, not the inactive one, is pro-amyloidogenic, and may even behave in some cases as a β-secretase-like [24].…”

“…Deciphering the pathophysiological mechanisms of Alzheimer's disease (AD) on which to base the design of efficient therapies represents a major scientific, societal and economic challenge. Amyloid beta peptide (Aβ) resulting from the cleavage of the amyloid beta precursor protein (APP), has long been considered to be the major pathogenic factor in AD, but other neurotoxic APP fragments are emerging in a context of more complex proteolytic processing of APP than expected (reviewed in [1][2][3]). APP cleavage by β-secretase generates a transmembrane β-C-terminal fragment of 99 amino acids (β-CTF/C99), which is then cleaved by γ-secretase to release monomeric forms of Aβ.…”

“…Membrane-type 5-matrix metalloproteinase (MT5-MMP, also known as MMP-24 or ηsecretase) is one of the newly discovered APP-cleaving enzymes [2]. Primarily expressed in neural cells [16,17], MT5-MMP contributes to physiological and pathological processes in the nervous system [18,19].…”