Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases

Abstract

Neurodegeneration is a chronic progressive loss of neuronal cells leading to deterioration of central nervous system (CNS) functionality. It has been shown that neuroinflammation precedes neurodegeneration in various neurodegenerative diseases. Matrix metalloproteinases (MMPs), a protein family of zinc-containing endopeptidases, are essential in (neuro)inflammation and might be involved in neurodegeneration. Although MMPs are indispensable for physiological development and functioning of the organism, they are often referred to as double-edged swords due to their ability to also inflict substantial damage in various pathological conditions. MMP activity is strictly controlled, and its dysregulation leads to a variety of pathologies. Investigation of their potential use as therapeutic targets requires a better understanding of their contributions to the development of neurodegenerative diseases. Here, we review MMPs and their roles in neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). We also discuss MMP inhibition as a possible therapeutic strategy to treat neurodegenerative diseases.

Figure 1

Classification of the MMPs based on their domain organization. MMPs are grouped into four major groups: gelatinases, matrilysins, archetypal MMPs, and furin-activatable MMPs. The typical structure of MMPs consists of a signal peptide, propeptide, a catalytic domain, hinge region, and a hemopexin domain. In addition, members of the gelatinases family have extra fibronectin type II motif repeats in the catalytic domain, and matrilysins have neither a hinge region nor hemopexin domains. Furin-activatable MMPs contain a furin recognition motif and are subcategorized into either secreted or membrane bound. Based on the type of membrane attachment, they are subdivided into type I transmembrane MMPs, GPI-linked MMPs, and type II transmembrane MMPs. Type-II transmembrane MMPs lack a cysteine switch. Instead, they have a cysteine rich domain and IgG-like domain. C, C-terminal domain; FN, fibronectin; GPI, glycophosphatidylinositol; MMP, matrix metalloproteinases; N, N-terminal domain.

Figure 2

Schematic representation of the activation of MMPs, their interactions with cytokines and chemokines, and the outcome of the interactions. MMPs are induced and activated in the presence of an external trigger (e.g., inflammatory stimuli) or abnormal proteins (e.g., protein or peptide aggregates). The activated MMPs can alter the properties of cytokines and chemokines. They also interact with the extracellular matrix, cell surface receptors, growth factors, integrin, signaling molecules, and tight junction proteins and alter their properties. This affects neuroinflammation, cell death or survival, growth, and regeneration. ECM, extracellular matrix; MMP, matrix metalloproteinase; TJs, tight junctions.

Figure 3

Schematic representation of the involvement of MMPs in Alzheimer's disease pathology. Aβ peptides produced from APP processing form oligomers that subsequently form amyloid deposits or plaques in the brain parenchyma. Aβ oligomers activate inflammatory cells in the brain (astrocytes, microglia, and choroid plexus epithelium). Once activated, microglia change their shape, migrate close to plaques, and begin to secrete proinflammatory cytokines and MMPs. Secreted MMPs degrade Aβ and, on the other hand, exacerbate inflammation in the brain, leading to death of neurons. These cytokines and MMPs also affect the endothelial tight junctions, alter the pericyte phenotypes, and contribute to increased BBB permeability. Similarly, oligomers in the CSF activate the choroid plexus epithelium, which leads to the release of proinflammatory cytokines and MMPs. These secreted MMPs further damage the tight junctions at the BCSFB. Aβ, β-amyloid; BBB, blood-brain barrier; BCSFB, blood-cerebrospinal fluid barrier; CSF, cerebrospinal fluid; MMP, matrix metalloproteinase; TJs, tight junctions.

Figure 4

Strategies for targeting MMPs. Inflammatory triggers or protein aggregates in neurodegenerative diseases initiate an inflammatory cascade. At this early stage, various pharmacological anti-inflammatory drugs are effective in eliminating the downstream consequences. Increased inflammation induces and/or activates MMPs, and various broad spectrum inhibitors are available to inhibit MMPs. However, due to the fact that MMPs have both beneficial and detrimental effects, specific MMP inhibition might be a better approach. Finally, it is also possible to interfere at the level of the cleaved substrates, either by reconstitution of crucial substrates or by blockage or removal of effector molecules.