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; Crouzin, Nadine; Carrete, Alex; Paumier, Jean Michel; Py, Nathalie A.; Bernard, Arnaud; Bauer, Charlotte; Charrat, Eliane; Moschke, Katrin; Seiki, Mothoharu; Vignes, Michel; Lichtenthaler, Stefan F.; Checler, Frédéric; Khrestchatisky, Michel; Rivera, Santiago

doi:10.1007/s00018-015-1992-1

Cited by 95 publications

(171 citation statements)

References 69 publications

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“…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.…”

Section: The App Cleavage Products Present In Exosomes Are Changed Bysupporting

confidence: 77%

“…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.…”

Section: Discussionsupporting

confidence: 55%

“…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.…”

Section: Ctf-α Is Greatly Enriched In Exosomes Secreted By Cortical Nmentioning

confidence: 65%

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

Laulagnier

Javalet

Hemming

et al. 2017

Cell. Mol. Life Sci.

130

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Section: The App Cleavage Products Present In Exosomes Are Changed Bysupporting

confidence: 77%

Section: Discussionsupporting

confidence: 55%

Section: Ctf-α Is Greatly Enriched In Exosomes Secreted By Cortical Nmentioning

confidence: 65%

See 1 more Smart Citation

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

Laulagnier

Javalet

Hemming

et al. 2017

Cell. Mol. Life Sci.

130

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“…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.…”

Section: T05-059cmentioning

confidence: 99%

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

2017

Glia

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The chronic inflammatory demyelinating disease multiple sclerosis is characterized by multifocal demyelinating lesions, loss of oligodendrocytes (OLG) and subsequent axonal damage. Remyelination occurs in MS lesions and requires proliferation, migration and differentiation of adult oligodendroglial progenitor cells (OPCs) into mature, myelinating oligodendrocytes. It has been shown that in acute lesions OPCs accumulate at the lesion border and fail to migrate sufficiently into demyelinated lesion areas. Therefore, promotion of the migratory capacity of OPCs into demyelinated areas could be a promising target of new therapy strategies to enhance remyelination. Furthermore, differences between oligodendroglial progenitor cell populations from different CNS locations have been recently emerged; however it is unclear whether this contributes to the variable extent of remyelination observed in MS lesions localized in different CNS regions. We used primary OPCs isolated from either cerebrum or spinal cord using the panning method. In our cultures we observed a significant and reproducible difference in the migratory capacity of OPCs originating from either cerebrum (cOPC) or spinal cord (scOPC) indicating a cell intrinsic mechanism of migratory capability. To date, it is postulated that OPC migration is regulated by complex interactions of inand extrinsic factors. Under the same environmental conditions in vitro, undirected as well as directed migration towards a PDGF gradient is strongly increased in scOPC. Exposure of other factors known to modulate OPC migration (e.g. bFGF, Endothelin-1) did not exhibit remarkable differences between cOPCs or scOPC. To identify candidate genes that contribute to the migratory phenotype of scOPCs we performed genes between cOPCs and scOPCs, which are involved in cell migration or polarity. These candidate genes were further verified by q-RT-PCR in neonatal as well as adult OPCs. One of the analyzed genes is Skap2, a scr-kinase associated protein, which is a downstream target of Fyn kinase and was previously identified to play a role in migration and adhesion of other cell types i.e. macrophages. In vitro lentiviral knockdown with Skap2 shRNAs decreased migration of OPCs, but did not influence differentiation into mature oligodendrocytes. Thus, our data indicates the potential involvement of Skap2 in regulation of OPC migration. Spinal cord injury (SCI) results in neural loss and consequently motor and sensory deficit below the injury. Here we have report the regenerative effects and significant improvement of locomotor function in complete transection rat model of SCI following transplantation of oligodendrocyte progenitors cells (OPC) and motoneuron progenitors (MP) derived from hESC. Transplantation of these progenitors promote astrogliosis, thorough activation of jagged1-dependent Notch and Jak/STAT signalling supporting axonal survival. Induction of astrogliosis and neurogenesis can be achieved by inhibition of glycogen synthase kinase-3 (GSK3) well known molecule involved in se...

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“…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.…”

Section: -Secretasementioning

confidence: 99%

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

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

150

122

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Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

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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

Cited by 95 publications

References 69 publications

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

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

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

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

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