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 bloodbrain 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.

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

“…MMPs digest the tight junctions and basement membrane proteins and thus further increase the BBB permeability in neuroinflammation (Rempe et al, 2016). MMP-3 is normally present in low concentration but increases in various inflammatory conditions.…”

“…MMP-3 is an inflammatory mediator released from activated microglia (Lee et al, 2010a) as well as mast cells (Johnson et al, 1998). MMPs are highly expressed in several neuropathological disorders and induces neuroinflammatory responses causing the breakdown of the BBB, infiltration of the peripheral immunocytes, demyelination, and neuronal death (Woo et al, 2008; Rosenberg, 2009; Rempe et al, 2016). The expression of MMP-3 is also upregulated in α-synuclein-stimulated microglia and mediates neuroinflammatory reactions relevant to PD.…”

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

“…MMP-2 and MMP-9 first tunnel the brain endothelial tight junctions and then cleave the receptor transmembrane β-dystroglycan, which anchors astrocytes' end feet to the basement membrane. Association studies repeatedly reported the present of a significant correlation between MMP-2 and MMP-9 with MS, further implementing the role of these molecules in disease development [52][53][54][55][56]. Other MMPs, including MMPs-1, 3, 9, 19, have also been implicated in BBB extravasation [52].…”

NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator‐induced haemorrhagic transformation after cerebral ischaemia

“…MMP9 and MMP2 are two structurally-similar MMPs regulating TJPs destruction and BBB integrity in tPA-associated haemorrhage (Rempe et al, 2016). The kinetic analysis based on a FRET-peptide fluorometric kit showed that delayed tPA treatment significantly enhanced the activities of MMP9 ( Figure 7A) and MMP2 ( Figure 7B).…”