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MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid ă 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.
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https://hal.archives-ouvertes.fr/hal-01477822
Contributor : Michel Khrestchatisky <>
Submitted on : Monday, June 25, 2018 - 5:51:43 PM
Last modification on : Tuesday, May 26, 2020 - 6:50:51 PM
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Kévin Baranger, Yannick Marchalant, Amandine E. Bonnet, Nadine Crouzin, Alex Carrete, et al.. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid ă pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease. Cellular and Molecular Life Sciences, Springer Verlag, 2016, 73 (1), pp.217-236. ⟨10.1007/s00018-015-1992-1⟩. ⟨hal-01477822⟩

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