ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Letronne, Florent; Laumet, Geoffroy; Ayral, Anne Marie; Chapuis, Julien; Demiautte, Florie; Laga, Mathias; Vandenberghe, Michel; Malmanche, Nicolas; Leroux, Florence; Eysert, Fanny; Sottejeau, Yoann; Chami, L.; Flaig, Amandine; Bauer, Charlotte; Dourlen, Pierre; Lesaffre, Marie; Delay, Charlotte; Huot, Ludovic; Dumont, Julie; Werkmeister, Elisabeth; Lafont, Frank; Mendes, Tiago; Hansmannel, Franck; Dermaut, Bart; Deprez, Benoı̂t; Hérard, Anne Sophie; Dhénain, Marc; Souedet, Nicolas; Pasquier, Florence; Tulasne, David; Berr, Claudine; Hauw, J. J.; Lemoine, Yves; Amouyel, Philippe; Mann, David A.; Déprez, Rebecca; Checler, Frédéric; Hot, David; Delzescaux, Thierry; Gevaert, Kris; Lambert, Jean‐Charles

doi:10.1016/j.ebiom.2016.06.002

Cited by 42 publications

(34 citation statements)

References 58 publications

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“…It remains to be investigated whether this might contribute to the differences between C83 and C99 levels in TgMT5 −/− mice. In pace with the importance of proteolytic enzymes in APP trafficking and amyloidogenesis, another APP-interacting metalloproteinase, ADAM30, has been shown to promote APP sorting to lysosomes and degradation (Letronne et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

Baranger

Bonnet

Girard

et al. 2017

Front. Mol. Neurosci.

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We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer’s disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP−/− mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aβ) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein (APP), including soluble APPα (sAPPα), sAPPβ and the MT5-MMP-linked fragment of 95 kDa, sAPP95. However, the lack of MT5-MMP did not affect the activity of β- and γ-secretases. In cultured HEKswe cells, transiently expressed MT5-MMP localized to early endosomes and increased the content of APP and Aβ40 in these organelles, as well as Aβ levels in cell supernatants. This is the first evidence that the pro-amyloidogenic features of MT5-MMP lie, at least in part, on the ability of the proteinase to promote trafficking into one of the amyloidogenic subcellular loci. Together, our data further support the pathogenic role of MT5-MMP in AD and that its inhibition improves the functional and pathological outcomes, in this case in the frontal cortex. These data also support the idea that MT5-MMP could become a novel therapeutic target in AD.

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Section: Discussionmentioning

confidence: 99%

MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

Baranger

Bonnet

Girard

et al. 2017

Front. Mol. Neurosci.

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“…In contrast to further subsequent cleavage of already released Aβ peptides, Cathepsin B (Hook et al, 2005, 2014; Kindy et al, 2012), S and L (Schechter and Ziv, 2011) have been discussed to be directly involved in Aβ generation, acting as alternative β-secretases. The enzymatic cleavage events of cathepsins on APP are not fully understood since some groups showed that cathepsins are rather involved in Aβ degradation lowering total Aβ burden (Mueller-Steiner et al, 2006; Letronne et al, 2016). …”

Section: Conventional App Processingmentioning

confidence: 99%

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Becker‐Pauly

Pietrzik

2017

Front. Mol. Neurosci.

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The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.

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“…Although we cannot exclude that other recently discovered APP-processing enzymes (e.g., meprin β, δ-secretase [1,39,2] might cooperate with MT5-MMP, this is rather unlikely because HEK cells do not constitutively express meprin β, and even when overexpressed, this metalloproteinase does not release sAPP95 [40,41]. Moreover, TIMPs do not inhibit meprins [42], while TIMP-2 efficiently blocked the generation of sAPP95 by MT5-MMP.…”

Section: The Generation Of Sapp95 By Mt5-mmp Does Not Involve Other Smentioning

confidence: 85%

“…Previous work reported the ability of the metalloproteinase ADAM30 to promote APP sorting in lysosomes by non-catalytic mechanisms. However, unlike MT5-MMP, the action of ADAM30 led to the degradation of APP by cathepsin D, thus preventing the formation of toxic APP catabolites[39]. Moonlighting actions of proteinases may logically require specific interactions of their non-catalytic domains with the target protein.…”

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confidence: 99%

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

García-González

Paumier

Louis

et al. 2020

Preprint

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We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

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ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Cited by 42 publications

References 58 publications

MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

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