MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-1992-1) contains supplementary material, which is available to authorized users.

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

“…Based on the immunoreactivity of the different CTFs, the amount of the 26 kDa fragment in APPwt exosomes was equivalent to that of CTF-β in APPswe exosomes. This reinforces the possibility that this fragment is indeed CTF-η, since it is a known substrate of β-secretase and the swe mutation enhances the processing of APP substrates by β-secretase [33,34]. Accordingly, incubation of APPswe-expressing N2a cells with a BACE-1 inhibitor almost abolished the presence of CTF-β while increasing CTF-η in exosomes (Fig.…”

“…Therefore, exosomes secreted by N2a cells overexpressing APP or by primary cortical cultures both contain CTF-α but no CTF-β. Instead, they contain a CTF with a molecular weight around 26 kDa, similar to the recently described CTF-η which is a product of the metallo-protease MT5-MMP and a substrate of BACE-1 [33,34]. The level of this fragment was increased in exosomes of APPswe N2a cells by the treatment with the BACE-1 inhibitor, further suggesting that it indeed corresponds to CTF-η.…”

“…The 13 kDa fragment corresponds to CTF-α produced by the α-secretase cleavage of APP which according to Hoey et al is by far the major form of CTFs found in cell lysates of cortical cultures [47]. The other fragment most likely corresponds to the recently characterized CTF-η (see below) [33,34]. APP fragments described in this study are represented in Fig.…”

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

“…Knockout of MT5-MMP in the 5xFAD mouse model of AD had positive effects, as it reduced both levels of the amyloid beta peptide (A ) and the amyloid precursor protein (APP) C-terminal fragment C99, as well as the inflammatory response. Strikingly, 5xFAD x MT5-MMP -/-mice had normal long-term potentiation and spatial learning without affecting the activity of -, -and -secretases (Baranger et al, 2016, Cell Mol Life Sci). At present we want to assess the effect of MT5-MMP modulation at the synaptic level in human cells.…”

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

“…Recent work from two groups revealed that -secretase contributes to the production of A␤, while also producing proteolytic fragments with the capacity to induce synaptic dysfunction (22,23). Both groups identified the matrix metalloproteinase MT5-MMP as contributing to the -secretase cleavage of APP.…”