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

Cell. Mol. Life Sci. (2016) 73:217236

DOI 10.1007/s00018-015-1992-1 Cellular and Molecular Life Sciences

RESEARCH ARTICLE

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Web End = MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimers disease

Kvin Baranger1 Yannick Marchalant1,8 Amandine E. Bonnet1 Nadine Crouzin1 Alex Carrete1

Jean-Michel Paumier1 Nathalie A. Py1 Anne Bernard1 Charlotte Bauer2 Eliane Charrat1 Katrin Moschke3,4

Mothoharu Seiki5 Michel Vignes6 Stefan F. Lichtenthaler3,4,7 Frdric Checler2 Michel Khrestchatisky1

Santiago Rivera1

Received: 26 May 2015 / Revised: 8 July 2015 / Accepted: 10 July 2015 / Published online: 23 July 2015 The Author(s) 2015. This article is published with open access at Springerlink.com

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 Alzheimers 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-decient mice and examined the impact of MT5-MMP deciency in bigenic 5xFAD/MT5-MMP-/- mice. At early stages (4 months) of the pathology, the levels of amyloid

beta peptide (Ab) 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-1b (IL-1b) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of a-, b- and c-secretases. The positive impact of MT5-MMP deciency 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 signicantly increased the levels of Ab and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were signicantly reduced in brain homogenates of 5xFAD/MT5-MMP-/- mice, supporting altogether the idea that MT5-MMP inuences APP processing. MT5-MMP emerges...