MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease

Kévin Baranger, Yannick Marchalant, Amandine E. Bonnet, Nadine Crouzin, Alex Carrete, Jean Michel Paumier, Nathalie A. Py, Anne Bernard, Charlotte Bauer, Eliane Charrat, Katrin Moschke, Mothoharu Seiki, Michel Vignes, Stefan F. Lichtenthaler, Frédéric Checler, Michel Khrestchatisky, Santiago Rivera

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageEnglish
Pages (from-to)217-236
Number of pages20
JournalCellular and Molecular Life Sciences
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Knockout mouse
  • MMP-24
  • Neurodegenerative disease
  • Neuroprotection
  • Synaptotoxicity

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