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

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

Cellular and molecular life sciences : CMLS, January 2016, Vol.73(1), pp.217-36 [Tạp chí có phản biện]

E-ISSN: 1420-9071 ; PMID: 26202697 Version:1 ; DOI: 10.1007/s00018-015-1992-1

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  • Nhan đề:
    MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease
  • Tác giả: Baranger, Kévin ; Marchalant, Yannick ; Bonnet, Amandine E ; Crouzin, Nadine ; Carrete, Alex ; Paumier, Jean-Michel ; Py, Nathalie A ; Bernard, Anne ; Bauer, Charlotte ; Charrat, Eliane ; Moschke, Katrin ; Seiki, Mothoharu ; Vignes, Michel ; Lichtenthaler, Stefan F ; Checler, Frédéric ; Khrestchatisky, Michel ; Rivera, Santiago
  • Chủ đề: Knockout Mouse ; Mmp-24 ; Neurodegenerative Disease ; Neuroprotection ; Synaptotoxicity ; Alzheimer Disease -- Enzymology ; Hippocampus -- Enzymology ; Matrix Metalloproteinases, Membrane-Associated -- Metabolism
  • Là 1 phần của: Cellular and molecular life sciences : CMLS, January 2016, Vol.73(1), pp.217-36
  • Mô tả: 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.
  • Ngôn ngữ: English
  • Số nhận dạng: E-ISSN: 1420-9071 ; PMID: 26202697 Version:1 ; DOI: 10.1007/s00018-015-1992-1

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