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

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

Abstract

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.

Keywords

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

Abbreviations

6-OHDA

6-Hydroxydopamine

5xFAD

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

AD

Alzheimer’s disease

Amyloid beta peptide

ADAM

A disintegrin and metalloproteinase

ADAMTS

ADAMs with thrombospondin motifs 

ALS

Amyotrophic lateral sclerosis

APOE

Apolipoprotein E

APP

Amyloid precursor protein

BACE-1

Beta-site APP cleaving enzyme 1

BBB

Blood–brain barrier

C3

BACE-1 inhibitor IV

CAA

Cerebral amyloid angiopathy

CNS

Central nervous system

CSF

Cerebrospinal fluid

CTF

C-terminal fragment

C99

APP-CTF of 99 amino acids

DAPT

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

DLB

Dementia with Lewy bodies

ECM

Extracellular matrix

FADD

Fas-associated protein with death domain

HD

Huntington’s disease

HD-NSCs

Neural stem cells from HD patients

HEKswe

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

Htt

Huntingtin

ICV

Intracerebroventricular

IDE

Insulin degrading enzyme

IL-1

Interleukin-1

LBs

Lewy bodies

LDLR

Low-density lipoprotein receptor

LRP-1

Low-density lipoprotein receptor-related protein 1

LRRK2

Leucine-rich repeat kinase 2

LTP

Long-term potentiation

MCP-1

Monocyte chemoattractant protein 1

MMP

Matrix metalloproteinase

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MSC

Mesenchymal stem cells

MT-MMP

Membrane-type matrix metalloproteinase

MTT

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

NFT

Neurofibrillary tangles

NSC

Neural stem cell

NTF

N-terminal fragment

PD

Parkinson’s disease

PGRN

Progranulin

Psen 1 and Psen 2

Presenilin 1 and 2

RAGE

Receptor for advanced glycation end products

sAPPα/β

Soluble APPα/β

TIMP

Tissue inhibitor of metalloproteinases

TNF-α

Tumour necrosis factor α

TREM2

Triggering receptor expressed on myeloid cells 2

Notes

Acknowledgements

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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