Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers

Abstract

Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

Keywords: Alzheimer’s; Blood–brain barrier; Parkinson’s disease; epilepsy; inflammation; intracranial aneurysm; multiple sclerosis; neurodegeneration; stroke.

Figure 1.

Matrix metalloproteinase structure. MMPs are divided into distinct structural groups: minimal-domain MMPs, hemopexin-domain-containing MMPs, gelatinases, and membrane-type MMPs. Minimal-domain MMPs contain an amino-terminal signal sequence (S) that directs them to the endoplasmic reticulum, a pro-peptide (Pro) that maintains them as inactive zymogens, and a catalytic domain with a zinc-binding site (Zn²⁺). In addition to the domains found in the minimal domain MMPs, hemopexin-domain-containing MMPs have a hemopexin-like domain that is connected to the catalytic domain via a hinge (h). This hinge region mediates the interactions with substrates, TIMPs, and cell-surface molecules. Gelatinase-type MMPs contain inserts that resemble collagen-binding type II repeats of fibronectin (FN). Membrane-type MMPs (MT-MMPs) have a domain that interacts with the membrane. Some MMPs also have a furin-cleavage site (F). MMPs found in the brain are highlighted in red.

Figure 2.

MMP-2 and MMP-9 promoter region with putative transcription factor binding sites. The boxes represent binding sites for the corresponding transcription factors. TSS: transcription start site; AP-1: activator protein 1; AP-2: activator protein 2; GATA-1: GATA-binding factor 1, erythroid transcription factor, globin transcription factor 1; SP-1: specificity protein 1; NF-κB: nuclear factor-κB, CREB: cyclic AMP response-element binding protein; p53: tumor protein p53 (modified after Peters et al. and Rosenberg).

Figure 3.

Blood–brain barrier anatomy. The blood–brain barrier is formed by capillary endothelial cells that are linked by tight junctions, surrounded by a basement membrane, and astrocytic endfeet. Astrocytes provide the cellular link to neurons; pericytes are embedded in the basement membrane. In disease, MMP protein expression and activity levels are increased, which is thought to result in blood–brain barrier leakage, possibly through degradation of tight junction and basement membrane proteins.

Figure 4.

MMPs in neuroinflammation. MMPs contribute to neuroinflammation through four mechanisms. (1) MMPs activate neuroinflammatory pathways and/or neurosignaling components. (2) MMPs act as signaling molecules themselves. (3) MMPs contribute to neuroinflammation-mediated neurotoxicity. (4) MMPs compromise vascular integrity resulting in blood–brain barrier leakage.

Figure 5.

MMPs in multiple sclerosis. (a) Brain endothelial cells and leukocytes secrete MMPs, which are thought to degrade tight junction and extracellular matrix proteins leading to extravasation of immune cells. (b) Leukocytes, microglia, neurons, and reactive astrocytes secrete MMPs, which demyelinate neuronal axons.

Figure 6.

MMP-9 in stroke. (a) acute phase: endothelial cells and recruited leukocytes secrete MMP-9, which degrades the blood–brain barrier, the neurovascular basement membrane, and the ECM. (b) remodeling phase: astrocytes and neurons secrete MMP-9, which contributes to remodeling of the ECM in the neurovascular unit.

Figure 7.

MMPs in cancer metastasis. MMPs participate in most steps of the cancer metastasis process. (1) Formation of metastatic cells at the primary tumor. (2) Intravasation of metastatic cells into the blood circulation. (3–6) Extravasation of metastatic cells across the blood–brain barrier into the brain. (7) Tumor cell migration in the brain. (8) MMPs contribute to the tumor microenvironment and tumor angiogenesis.