Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other neurodegenerative disorders

• Published in: Cellular and molecular life sciences : CMLS Vol. 76; no. 16; pp. 3167 - 3191
• Main Authors: Rivera, Santiago, García-González, Laura, Khrestchatisky, Michel, Baranger, Kévin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2019; Springer Nature B.V; Springer Verlag
• Subjects: ADAM protein; ADAM Proteins - metabolism; Age; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyotrophic lateral sclerosis; Biochemistry; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Biomedicine; Brain; Cell Biology; Disease; Disruption; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Inflammation; Inhibitors; Life expectancy; Life Sciences; Life span; Matrix metalloproteinase; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Medical innovations; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurological diseases; Neurons and Cognition; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Protein folding; Proteinase; Review; Scaffolding; Target recognition; Therapeutic applications; Thrombospondin; Tissue inhibitor of metalloproteinases; Tissue Inhibitor of Metalloproteinases - metabolism; ADAM; Amyotrophic lateral sclerosis; Huntington’s disease; Neurodegenerative brain disease; Parkinson’s disease; TIMP
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03178-2

As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood–brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease.