Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives

Abstract

Neurodegeneration is the pathological condition, in which the nervous system or neuron loses its structure, function, or both, leading to progressive degeneration or the death of neurons, and well-defined associations of tissue system, resulting in clinical manifestations. Neuroinflammation has been shown to precede neurodegeneration in several neurodegenerative diseases (NDs). No drug is yet known to delay or treat neurodegeneration. Although the etiology and potential causes of NDs remain widely indefinable, matrix metalloproteinases (MMPs) evidently have a crucial role in the progression of NDs. MMPs, a protein family of zinc (Zn2+)-containing endopeptidases, are pivotal agents that are involved in various biological and pathological processes in the central nervous system (CNS). The current review delineates the several emerging evidence demonstrating the effects of MMPs in the progression of NDs, wherein they regulate several processes, such as (neuro)inflammation, microglial activation, amyloid peptide degradation, blood brain barrier (BBB) disruption, dopaminergic apoptosis, and α-synuclein modulation, leading to neurotoxicity and neuron death. Published papers to date were searched via PubMed, MEDLINE, etc., while using selective keywords highlighted in our manuscript. We also aim to shed a light on pathophysiological effect of MMPs in the CNS and focus our attention on its detrimental and beneficial effects in NDs, with a special focus on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS), and Huntington’s disease (HD), and discussed various therapeutic strategies targeting MMPs, which could serve as potential modulators in NDs. Over time, several agents have been developed in order to overcome challenges and open up the possibilities for making selective modulators of MMPs to decipher the multifaceted functions of MMPs in NDs. There is still a greater need to explore them in clinics.

The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

“…MMPs can promote BBB breakdown through degradation of tight junction and basal lamina proteins and thereby facilitate leukocyte infiltration [ 282 ]. Augmented MMP expression is a feature of neuroinflammatory and neurodegenerative disorders, including AD, PD and MS [ 307 ]. For instance, monocytes with enhanced MMP-1, -3, -7 and -9 mRNA expression are more frequent in MS compared to control patients [ 308 ].…”

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

“…MPTP is bio transformed into an active toxic metabolite named 1-methyl-4-phenylpyridinium ion (MPP+), which belongs to the family of mitochondrial complex-I suppressors, and is exclusively involved in devastating DArgic nerve cells within the SN [ 106 , 107 ]. The exploration of MPTP as a triggering factor for degeneration within the SN encouraged the postulation that PD might be precipitated by toxic substances present in the environment [ 108 ].…”

Neurotrophic factor levels in the serum and cerebrospinal fluid of neonates infected with human cytomegalovirus

“…It is activated to degrade the extracellular matrix and participates in the pathological processes of many diseases. A previous study has shown that MMP‐3 acts as a conductive molecule in neuronal apoptosis gene expression and inflammatory processes 25 . After infection with Epstein‐Barr virus and varicella zoster virus, MMP‐3 induced a significant upregulation of keratinocyte endothelial cells and cerebral vascular adventitial fibroblasts at the transcriptional level, which promoted cell migration and invasion, as well as aneurysm and stroke 26,27 .…”