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

  • Santiago RiveraEmail author
  • Laura García-González
  • Michel Khrestchatisky
  • Kévin Baranger


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.


Parkinson’s disease Huntington’s disease Amyotrophic lateral sclerosis ADAM TIMP Neurodegenerative brain disease 





Transgenic mice bearing 5 familial mutations on human App and Psen1 genes


Alzheimer’s disease

Amyloid beta peptide


A disintegrin and metalloproteinase


ADAMs with thrombospondin motifs 


Amyotrophic lateral sclerosis


Apolipoprotein E


Amyloid precursor protein


Beta-site APP cleaving enzyme 1


Blood–brain barrier


BACE-1 inhibitor IV


Cerebral amyloid angiopathy


Central nervous system


Cerebrospinal fluid


C-terminal fragment


APP-CTF of 99 amino acids


N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, γ-secretase inhibitor


Dementia with Lewy bodies


Extracellular matrix


Fas-associated protein with death domain


Huntington’s disease


Neural stem cells from HD patients


Human embryonic kidney cells that express App gene with the Swedish mutation






Insulin degrading enzyme




Lewy bodies


Low-density lipoprotein receptor


Low-density lipoprotein receptor-related protein 1


Leucine-rich repeat kinase 2


Long-term potentiation


Monocyte chemoattractant protein 1


Matrix metalloproteinase




Mesenchymal stem cells


Membrane-type matrix metalloproteinase


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide


Neurofibrillary tangles


Neural stem cell


N-terminal fragment


Parkinson’s disease



Psen 1 and Psen 2

Presenilin 1 and 2


Receptor for advanced glycation end products


Soluble APPα/β


Tissue inhibitor of metalloproteinases


Tumour necrosis factor α


Triggering receptor expressed on myeloid cells 2



This work was supported by funding from the CNRS and Aix-Marseille Université and by public grants overseen by the French National Research Agency (ANR), MAD5 to SR, and PREVENTAD to MK, as part of the second “Investissements d’Avernir” program. The work was also supported by the DHUNE Centre of Excellence and grants from CoEN, “Fondation Plan Alzheimer”, France Alzheimer and Vaincre l’Alzheimer to SR. KB was granted a research associate fellowship (Management of Talents) by the Initiative d’Excellence of Aix-Marseille University - A*MIDEX, a French “Investissements d’Avenir” programme.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Aix-Marseille Univ, CNRS, INP, Inst NeurophysiopatholMarseilleFrance

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