title: MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.
abstract: Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimer's disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of MT5-MMP deficiency was still noticeable at 16 months of age, as illustrated by reduced amyloid burden and gliosis, and a better preservation of the cortical neuronal network and synaptophysin levels in bigenic mice. MT5-MMP expressed in HEKswe cells colocalized and co-immunoprecipitated with APP and significantly increased the levels of Aβ and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were significantly reduced in brain homogenates of 5xFAD/MT5-MMP(-/-) mice, supporting altogether the idea that MT5-MMP influences APP processing. MT5-MMP emerges as a new pro-amyloidogenic regulator of APP metabolism, whose deficiency alleviates amyloid pathology, neuroinflammation and cognitive decline.
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Baranger
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.|Psychology Department, Central Michigan University, Mount Pleasant, MI, 48859, USA.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marchalant
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Amandine E
authors.initials: AE
authors.lastname: Bonnet
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Crouzin
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Alex
authors.initials: A
authors.lastname: Carrete
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Paumier
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Py
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Labex DistAlz, IPMC UMR 7275 CNRS-UNS, 06560, Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Charrat
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, Munich, Germany.|Klinikum rechts der Isar, and Institute for Advanced Study, Technische Universität München (TUM), 81675, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Moschke
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Mothoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: UMR5247 IBMM CNRS University of Montpellier 1 and University of Montpellier 2, 34095, Montepellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vignes
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) and Neuroproteomics, Munich, Germany.|Klinikum rechts der Isar, and Institute for Advanced Study, Technische Universität München (TUM), 81675, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Labex DistAlz, IPMC UMR 7275 CNRS-UNS, 06560, Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.affiliation: Aix-Marseille Université, CNRS, NICN UMR 7259, 13344, Marseille, France. santiago.rivera@univ-amu.fr.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000378:metabolism; D000818:Animals; D003071:Cognition; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006624:Hippocampus / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065853:Spatial Learning
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D053504:Matrix Metalloproteinases, Membrane-Associated; C118502:Mmp24 protein, mouse
keywords: Knockout mouse; MMP-24; Neurodegenerative disease; Neuroprotection; Synaptotoxicity