Metalloproteinases and their tissue inhibitors in Alzheimer's disease and other neurodegenerative disorders

Abstract

As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.

Keywords: ADAM; Amyotrophic lateral sclerosis; Huntington’s disease; Neurodegenerative brain disease; Parkinson’s disease; TIMP.

Fig. 1

Schematic model summarizing the potential roles of MT1- and MT5-MMP in APP processing and the amyloidogenic pathway. 1: Canonical amyloid precursor protein (APP) and MT-MMPs are targeted from the trans-Golgi network (TGN) to the plasma membrane or directly to the endosomal pathway. 2: On the plasma membrane, MT-MMPs generate a soluble APP fragment of 95 kDa (sAPP95), either alone or in concert with MMP-2, and the residual transmembrane fragment of 30 kDa (CTF-30/η-CTF). 3: Also at the membrane level, APP can be processed by α-secretase through the canonical pathway that generates sAPPα and the transmembrane α-CTF/C83. In addition, the combined action of MT-MMPs and α-secretase could generate a synaptotoxic peptide (Aη-α). 4: MT-MMPs could promote the internalization of CTF-30/η-CTF or unprocessed APP in early endosomes (5), where β-secretase generates sAPPβ, β-CTF/C99 or Aη-β. β-secretase processing of APP may also occur in multivesicular bodies (MVB) (6), followed by γ-secretase cleavage (7) to generate beta amyloid peptide (Aβ) and APP intracellular domain (AICD). The latter may be also generated in the lysosomes (8) and translocated into the nucleus (9). Aβ and sAPPβ can be degraded by lysosomes (10) or released into the extracellular space (11). CTF-30/η-CTF and Aβ can also be released in exosomes (12). Note that generation of η-fragments has only been reported for MT5-MMP so far. The contribution of MMP-2 to sAPP95 production has been described in association with MT1-MMP, and it remains to be determined whether this could also be the case for MT5-MMP. For the sake of simplicity, the cartoon does not show late and recycling endosomes, the possible location of γ-secretase on the plasma membrane or APP trafficking between the endosomal system and the TGN. This scheme includes freely available objects from Servier Medical Art templates (https://smart.servier.com)