MMPs in Neurodegenrative Diseases

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. MMPs are essential in (neuro)inflammation and might be involved in neurodegeneration. Increased expression of MMPs is observed in a variety of pathological conditions, including neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and multiple sclerosis (MS). 

MMPs are major factors in the pathological processes that occur in the brain with hypoxia/ischemic injury, multiple sclerosis, infection, and vascular causes of dementia.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Its prominent characteristics include brain atrophy, caused by neuronal cell death, and decreased dendritic arborization in the cerebral cortex and other subcortical areas. The hallmarks of AD include presence of amyloid plaques and neurofibrillary tangles, which are linked to cerebral atrophy.
MMP-9 and TIMP-1 as biomarkers of AD. MMP-9 expression was shown to be induced in AD patients in neuronal cytoplasm, neurofibrillary tangles, amyloid plaques, and vascular tissue, as well as in astrocytes upon Aβ stimulation. MMP-9 was found in pyramidal neurons of the brains of AD patients. Notable increase in MMP-1 in brain of AD patients. MMP-3 can degrade Aβ. 

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and the most common neurodegenerative movement disorder, with an estimated 7–10 million people worldwide suffering from it. A prominent characteristic of PD is the presence of intracellular protein inclusions called Lewy bodies in affected brain areas. Another hallmark of PD is selective and progressive loss of dopaminergic neurons in substantia nigra pars compacta. The substantia nigra, being part of basal ganglia together with the striatum, globus pallidus, and subthalamic nucleus, modulates motor activity in the brain. Thus, due to dopaminergic neuron cell death, one of the clear manifestations of the disease is loss of control over movements, resting tremor, bradykinesia, and rigidity.
MMP-3, produced by neurotoxin-stressed dopaminergic neurons, seems to be a self-sufficient player in microglial activation in the absence of any other inflammatory molecule. MMP-9 is expressed in reactive microglia and astrocytes, pinpointing MMP-9 as a key molecule for the onset of neuroinflammation in PD. The proteolytic activity of MMPs might be involved in alteration of α-synuclein protein conformation, thus contributing to aggregation, Lewy body formation, and microglial activation. MMP-3 was particularly efficient, MMP-1, MMP-2, and MMP-14 showed similar properties.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is characterized by degeneration of motor neurons in the brain, brainstem, and spinal cord. All voluntary muscles are affected, and the muscle weakness and atrophy are followed by paralysis, and finally respiratory failure and death. 
MMP-2 and MMP-9 as well as their tissue inhibitors as potential biomarkers of ALS.

Multiple sclerosis (MS) is a neuroinflammatory auto-immune disease that affects about 1.3 million people worldwide. In MS, the myelin sheaths that cover neuronal axons and nerve fibers in the brain and spinal cord are damaged, which disrupts communication and causes a wide range of disease symptoms.
MMPs digest myelin basic protein, which causes demyelination and drives MS progression. One characteristic of MS is leukocyte extravasation and transmigration across the brain endothelium into the CNS. MMPs may facilitate this process by activating adhesion molecules and degrading the basement membrane that surrounds blood vessels. 
Samples from MS patients consistently found increased protein levels for MMPs-2, -3, -7, -9, -12, -13. In addition, in lesional MS tissue, MMPs-1, -2, -3, -9, and -19 have been detected in microglial nodules and microglial-like cells where they contribute to inflammation and further destabilize the blood–brain barrier.

Huntington’s disease (HD) is an inherited neurodegenerative disorder that decreases muscle coordination and mental ability. The disease has been linked to a mutation on chromosome 4 in a gene coding for a protein called huntingtin (Htt). MMPs have a distinctive role in cleavage of Htt. 
Knocking down MMP-10, MMP-14, and MMP-23 in cultured striatal cells expressing mutant Htt diminishes toxicity. 
Significantly elevated levels of MMP-9 were found in plasma of patients suffering from HD, it was proposed as a potential biomarker of HD.

Other Neurodegenrative Diseases Related proteins

Aβ amiloid peptides
α-synuclein
Cu,Zn SOD1 wt
SOD1 G93A mutant        
SOD1 D90A mutant        
SOD1 G37R mutant        
SOD1 G85R mutant        
SOD1 A4V mutant
SOD1 A89V mutant        
SOD1 E100G mutant      
SOD1 G93R mutant        
SOD1 G93D mutant        
SOD1 I113F mutant       
SOD1 I113T mutant       
SOD1 I35T mutant          
SOD1 L144F mutant      
SOD1 L148I mutant       
SOD1 T54R mutant        
SOD1 V87M mutant
SOD1 V97M mutant

References

Brkic M., Balusu S., Libert C., Vandenbroucke R.E. Friends or foes: Matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediat. Inflamm. 2015;2015:620581.
Łukaszewicz-Zając M, Mroczko B, Słowik A. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in amyotrophic lateral sclerosis (ALS). J Neural Transm (Vienna). 2014 Nov;121(11):1387-97.
Liuzzi G.M., Trojano M., Fanelli M., Avolio C., Fasano A., Livrea P., Riccio P. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: Implication for pathogenesis. Mult. Scler. 2002;8:222–228.
Pauline Zipfel, Christophe Rochais, Kévin Baranger, Santiago Rivera, and Patrick Dallemagne, Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges, J. Med. Chem. 2020, 63, 19, 10705–10725