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

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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.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

5xFAD:

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

AD:

Alzheimer’s disease

Aβ:

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

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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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  1. Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France

    Santiago Rivera, Laura García-González, Michel Khrestchatisky & Kévin Baranger

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Rivera, S., García-González, L., Khrestchatisky, M. et al. Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other neurodegenerative disorders. Cell. Mol. Life Sci. 76, 3167–3191 (2019). https://doi.org/10.1007/s00018-019-03178-2

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