title: MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Traffickingin vitro.
abstract: We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer's disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP-/-mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aβ) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein (APP), including soluble APPα (sAPPα), sAPPβ and the MT5-MMP-linked fragment of 95 kDa, sAPP95. However, the lack of MT5-MMP did not affect the activity of β- and γ-secretases. In cultured HEKswe cells, transiently expressed MT5-MMP localized to early endosomes and increased the content of APP and Aβ40 in these organelles, as well as Aβ levels in cell supernatants. This is the first evidence that the pro-amyloidogenic features of MT5-MMP lie, at least in part, on the ability of the proteinase to promote trafficking into one of the amyloidogenic subcellular loci. Together, our data further support the pathogenic role of MT5-MMP in AD and that its inhibition improves the functional and pathological outcomes, in this case in the frontal cortex. These data also support the idea that MT5-MMP could become a novel therapeutic target in AD.
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Baranger
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Amandine E
authors.initials: AE
authors.lastname: Bonnet
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Stéphane D
authors.initials: SD
authors.lastname: Girard
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Paumier
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Laura
authors.initials: L
authors.lastname: García-González
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, Laboratory of excellence DistALZ, Sophia-Antipolis Valbonne, France.
authors.forename: Wejdane
authors.initials: W
authors.lastname: Elmanaa
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Charrat
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Stephan
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, Laboratory of excellence DistALZ, Sophia-Antipolis Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Moschke
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE)Munich, Germany; Neuroproteomics, Klinikum rechts der Isar, and Institute for Advanced Study, Technische Universität München (TUM)Munich, Germany; Munich Cluster for Systems Neurology (SyNergy)Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: François S
authors.initials: FS
authors.lastname: Roman
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, Laboratory of excellence DistALZ, Sophia-Antipolis Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259 Marseille, France.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
keywords: amyloid beta peptide; amyloid precursor protein; endosomes; learning and memory; matrix metalloproteinase; transgenic mice