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Cited by 28Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsProtease and Inhibitor Mechanisms

The DOI matches its Crossref record; 76 of the 78 references it cites were found in a registry or an index; 8 of the 86 sources its claims cite were checked for support.

MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer’s disease

Open access
Pilat, Dominika, Paumier, Jean-Michel, García-González, Laura, Louis, Laurence, Stephan, Delphine, Manrique, Christine, Khrestchatisky, Michel, Di Pasquale, Eric, Baranger, Kévin, Rivera, Santiago·2022·Journal of Neuroinflammation
DOI 10.1186/s12974-022-02407-zPMC PMC8915472
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Abstract

Background: Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation. Methods: To test this hypothesis, we used 11–14 day in vitro primary cortical cultures from wild type, MT5-MMP −/− , 5xFAD and 5xFAD/MT5-MMP −/− mice, and evaluated the impact of MT5-MMP deficiency and IL-1β treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction. Results: 5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment. Conclusions: Neuroinflammation and hyperexcitability precede Aβ accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism. In addition, MT5-MMP deficiency prevents IL-1β-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In primary cortical neuron/astrocyte cultures from 5xFAD and MT5-MMP–deficient mice, MT5-MMP deficiency reduced basal neuroinflammation, Aβ levels, and 5xFAD-associated neuronal hyperexcitability, while IL-1β effects were largely blunted except for exacerbated event frequency. The authors conclude MT5-MMP sits at the crossroads of early AD-related inflammation, APP/Aβ metabolism, and neuronal activity.

Key findings

  • 5xFAD cultures showed a 76% increase in MT5-MMP protein versus WT. MT5-MMP deficiency reduced Aβ40 by 48% in MT5−/− and 41% in TgMT5−/− cells versus WT and Tg, respectively, and reduced Aβ42 by 44% in TgMT5−/− versus Tg; IL-1β did not affect Aβ levels.
  • MT5-MMP-deficient cultures had lower basal inflammatory mediators: in TgMT5−/− versus Tg, Il-1β mRNA was decreased by 77%, Ccl2 by 63%, and Il-6 by 52%; IL-1β protein was 87% lower in TgMT5−/− versus Tg. IL-1β-induced Ccl2 was reduced by 55% in MT5−/− and 49% in TgMT5−/− versus respective controls.
  • Untreated 5xFAD neurons showed hyperexcitability: gPSC peak amplitude was 69% higher and frequency 536% higher than WT. TgMT5−/− neurons did not show this increase, with 72% lower amplitude and 75% lower frequency than Tg. IL-1β increased gPSC frequency by >1000% in both MT5−/− and TgMT5−/− cells.
  • AAV-C99 overexpression showed MT5-MMP deficiency reduced C99 by 56% in MT5−/− versus WT neurons; with DAPT, C99 and C83 were reduced by 39% and 38%, respectively, and human Aβ40 was decreased by 62% in MT5−/− AAV-C99 cells versus WT.

Methods

  • Mixed neuron/astrocyte primary cortical cultures from WT, MT5−/−, 5xFAD (Tg), and 5xFAD/MT5-MMP−/− (TgMT5−/−) mice were used at 11–14 days in vitro; cultures were roughly 2/3 neurons and 1/3 astrocytes, with no microglia detected.
  • Cells were treated with IL-1β (10 ng/mL for 24 h), DAPT (10 μM), MG132 (5 μM), or transduced with AAV-empty/AAV-C99.
  • Analyses included whole-cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry, subcellular fractionation, and MTT viability assays; statistics used ANOVA with Fisher’s LSD post hoc test, p < 0.05.

Limitations

  • Stated: the authors note the experimental setting used a single IL-1β concentration and that the complexity of cytokine effects must be interpreted within the limitations of their system.
  • Stated: they could not exclude that a small, western-blot–undetectable pool of sAPP95/sAPPη reaches the synapse, and they state no general conclusion can be drawn about the correlation between capacitance and gPSCs because it was not validated in all groups.
  • Evident from the text: the cultures lack microglia, so the neuroinflammatory findings are restricted to neuron/astrocyte interactions; the study is an in vitro developing-cell model, not adult brain tissue, and basal C99 was not detectable without overexpression.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12974-022-02407-z

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

8 of 86 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    MT5-MMP can modulate neuronal activity.

    “We and others previously reported that MT5-MMP can modulate neuronal activity [8, 9, 12, 13].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [8] Monea S, Jordan BA, Srivastava S, DeSouza S, Ziff EB. Membrane localization of membrane type 5 matrix metalloproteinase by AMPA receptor binding protein and cleavage of cadherins. J Neurosci. 2006;26:2300–12. source
    • cites [9] Restituito S, Khatri L, Ninan I, Mathews PM, Liu X, Weinberg RJ, et al. Synaptic autoregulation by metalloproteases and γ-secretase. J Neurosci. 2011;31:12083–93. source
    • cites [12] Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, et al. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015;526(7573):443–7. source
    • cites [13] Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier J-M, et al. 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(1):217–36. source
  • Findingown data

    IL-1β treatment significantly exacerbated gPSC frequency in all genotypes.

    “IL-1β treatment significantly exacerbated frequency in all genotypes”
    Quote in the paperSubstantial claim
  • Findingown data

    MT5-MMP deficiency significantly reduced Aβ40 levels by 41% in TgMT5−/− cells compared with Tg cells.

    “However, MT5-MMP deficiency significantly reduced Aβ40 levels in MT5−/− (48%) and TgMT5−/− (41%) cells, compared with WT and Tg cells, respectively (Fig. 6C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Ccl2 mRNA is decreased by 63% in TgMT5−/− cells compared with Tg cells.

    “Similarly, Ccl2 mRNA, which encodes monocyte chemoattractant protein-1 (MCP-1) (Fig. 2B) and Il-6 mRNA were respectively significantly decreased by 63% and 52% in TgMT5−/− cells, compared with Tg (Fig. 2C).”
    Quote in the paperSubstantial claim
  • Findingown data

    IL-1β challenge strongly upregulated MCP-1 levels in all genotypes.

    “Inflammatory challenge with IL-1β strongly upregulated MCP-1 levels in all genotypes”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim. 47
  • It may state two separate claims as one. 47
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    MT5-MMP cleaves APP to generate an η-CTF, which is processed by α-secretase to release an Aη-α fragment that inhibits LTP in cellulo.

    “Alternatively to canonical APP processing, MT5-MMP has been shown to cleave APP and to generate an η-CTF from which subsequent processing by α-secretase releases an Aη-α fragment that inhibits LTP in cellulo [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, et al. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015;526(7573):443–7. source

      The passages on APP processing report that MT5-MMP contributes to η-secretase cleavage and that α-secretase processing of CTF-η releases Aη-α. The LTP passage reports inhibition when Aη-α was applied to hippocampal slices ex vivo, not an in-cellulo LTP experiment as the claim specifies. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Cellular receptors such as LRP1, LRP8, LDLR and RAGE may affect APP metabolism by modulating β- and γ-secretase activities and/or directly Aβ levels through endocytosis.

    “Cellular receptors such as low-density lipoprotein receptor-related protein 1 (LRP1) [47–50], LRP8 [51], LDLR [52] or RAGE [53] may also affect APP metabolism by either modulating the activities of β- and γ-secretase and/or directly Aβ levels through endocytosis.”
    Quote in the paperNot a substantial claim6 of 6 sources checked
    • cites [47] Storck SE, Meister S, Nahrath J, Meißner JN, Schubert N, Di Spiezio A, et al. Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier. J Clin Invest. 2015;126(1):123–36. source
    • cites [48] Liu C-C, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, et al. Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. J Neurosci. 2017;37(15):4023–31. source
    • cites [49] Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res. 2017;58(7):1267–81. source
    • cites [50] Van Gool B, Storck SE, Reekmans SM, Lechat B, Gordts PLSM, Pradier L, et al. LRP1 has a predominant role in production over clearance of Aβ in a mouse model of Alzheimer’s disease. Mol Neurobiol. 2019;56(10):7234–45. source
    • cites [51] Fuentealba RA, Barría M, Lee J, Cam J, Araya C, Escudero CA, et al. ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity. Mol Neurodegener. 2007;2(1):14. source
    • cites [52] Katsouri L, Georgopoulos S. Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer’s Disease mouse model. PLoS ONE. 2011;6(7):e21880. source

      The Discussion (page unavailable) says LDLR affects amyloid deposition and may act with LRP1 in Aβ clearance, supporting a possible effect on Aβ levels. But it does not establish endocytosis as the mechanism. The Results (page unavailable) report no effect of LDLR deletion on APP processing or α- and β-secretase activity; they do not support the proposed secretase mechanism. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    MT5-MMP deficiency prevents basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.

    “Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In cortical primary neuron cultures, the mean peak amplitude of miniature global post-synaptic currents (gPSCs) ranged from −7 pA to −25 pA, with the maximum in Tg neurons and the minimum in the two MT5-MMP-deficient genotypes.

    “The mean peak amplitude of gPSCs ranged from − 7 pA to − 25 pA, with a maximum value for Tg neurons and a minimum for the two MT5-MMP-deficient genotypes (Fig. 5E).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Aβ38 was not detected in our cultures.

    “Aβ38 was not detected in our cultures (not shown)”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Cultures are roughly 2/3 neurons and 1/3 astrocytes, with no microglia detected.

    “Cultures were roughly estimated at 2/3 of neurons (β-III tubulin+) and 1/3 of astrocytes (GFAP+), while no microglia was detected (Iba1+).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Endogenous IL-1β concentration is around 500 pg/mL in WT and MT5−/− cells, and 259% higher in Tg cells.

    “The concentration of endogenous IL-1β was around 500 pg/mL in WT and MT5−/− cells, and 259% higher in Tg cells.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The increase in IL-1β in Tg cells is prevented in TgMT5−/− cells, whose values are 87% lower than Tg.

    “Such increase was prevented in TgMT5−/− cells, whose values were 87% lower than Tg (Fig. 3B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The level of N-cadherin 40 kDa (NCad 40 kDa) remained stable across genotypes and treatments except in Tg cells, where combined MG132 and IL-1β caused a 43% decrease compared with MG132 alone.

    “The level of N-cadherin 40 kDa (NCad 40 kDa) remained stable across genotypes and treatments except in Tg cells, where combined MG132 and IL-1β caused a 43% decrease compared with MG132 alone.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    After IL-1β treatment, no differences were observed between genotypes in input resistance, which averaged around 500-600 MΩ, except in TgMT5−/−, where IL-1β treatment prevented the increase in cell resistance observed in untreated cells.

    “After IL-1β treatment, no differences were observed between genotypes, which averaged around 500–600 MΩ, with the notable exception of TgMT5−/−, where IL-1β treatment prevented the increase in cell resistance observed in untreated cells (Fig. 5C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    IL-6 levels are very low and unchanged in all experimental conditions.

    “IL-6 levels were comparatively very low and unchanged in all experimental conditions (Fig. 3C).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    A single band of gelatinolysis with the expected molecular weight of pro-MMP-2 appeared in highly sensitive gelatin zymograms, and this band remained stable across genotypes or after IL-1β treatment.

    “a single band of gelatinolysis with the expected molecular weight of pro-MMP-2 appeared in highly sensitive gelatin zymograms, and this band remained stable across genotypes or after IL-1β treatment (Fig. 3I)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Basal MCP-1 levels are below 2000 pg/mL in WT and MT5−/− cells, and close to 3000 pg/mL in Tg cells, not significantly different from WT.

    “Basal MCP-1 levels were below 2000 pg/mL in WT and MT5−/− cells, while reaching values close to 3000 pg/mL in Tg cells, which were not significantly different from WT (Fig. 3A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The increase in basal gPSC frequency was prevented in TgMT5−/− neurons, where levels decreased by 75% compared with Tg neurons.

    “Again, the increase was prevented in TgMT5−/− neurons, where the levels decreased by 75% with respect to Tg.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Ccl2 mRNA levels increase by 5000% in WT and 4000% in Tg cells after IL-1β exposure.

    “Ccl2 mRNA levels, which were relatively low in basal conditions, respectively reached 5000% and 4000% increases in WT and Tg cells after IL-1β exposure (Fig. 2F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    MT5-MMP levels are increased by 76% in Tg cells compared to WT, and this increase is maintained under IL-1β.

    “also found a 76% increase of MT5-MMP levels in Tg cells compared to WT that was maintained under IL-1β (Fig. 1B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    IL-1β treatment prevented the increase in gPSC peak amplitude in Tg neurons, decreasing levels to 64% of the value in untreated Tg neurons.

    “Likewise, the increase in peak amplitude in Tg neurons was prevented by IL-1β, which decreased levels to 64% of the value in untreated Tg neurons (Fig. 5E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    IL-1β treatment upregulates Il-6 levels by 318% in WT, 79% in MT5−/− and 188% in TgMT5−/− cells, but has no effect in Tg cells.

    “IL-1β treatment upregulated Il-6 levels by 318% in WT, 79% in MT5−/− and 188% in TgMT5−/− cells, but had no effect in Tg cells, whose Il-6 levels were down by 45% compared to IL-1β-treated WT (Fig. 2G).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    There was a 38% reduction in IL-6 levels in Tg compared to WT.

    “the major change was the 38% reduction in Tg levels compared to WT”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Mmp14 mRNA remains stable in all genotypes and does not compensate for MT5-MMP deficiency, regardless of IL-1β treatment.

    “Mmp14 mRNA remained stable in all genotypes and thus did not compensate for MT5-MMP deficiency, regardless of IL-1β treatment (Fig. 1C).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    IL-1β induces its own mRNA in WT (174%) and Tg (109%) cultures, but not in cells lacking MT5-MMP (MT5−/− and TgMT5−/−).

    “IL-1β induced its own mRNA in WT (174%) and Tg (109%) cultures (Fig. 2E), but not in cells lacking MT5-MMP (MT5−/− and TgMT5−/−) (Fig. 2E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The absence of MT5-MMP significantly reduces Aβ by more than 40% while sparing APP metabolism.

    “Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Cell lysates revealed a 46% reduction of IL-1β levels in TgMT5−/− cells compared with Tg, while no differences were observed between MT5−/− and WT cells.

    “cell lysates also revealed a 46% reduction of IL-1β levels in TgMT5−/− cells compared with Tg, while no differences were observed between MT5−/− and WT cells (Fig. 3G)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    DAPT treatment caused a 168% increase in C99 and a 1300% increase in C83 in WT cells compared to untreated AAV-C99 cells.

    “Conversely, DAPT treatment caused a 168% and 1300% increase in C99 and C83 in WT cells compared to untreated AAV-C99 cells, respectively (Fig. 8A–C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    LRP8 protein was undetectable in the experimental conditions.

    “In our experimental conditions, LRP8 was undetectable”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    This high accumulation of CTFs was significantly reduced in MT5−/− cells by 39% for C99 and 38% for C83.

    “This high accumulation of CTFs was significantly reduced in MT5−/− cells by 39% for C99 and 38% for C83.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Basal Aβ42 levels were approximately tenfold lower than Aβ40 levels.

    “Basal Aβ42 levels were approximately tenfold lower than those of Aβ40.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The content of β-III tubulin and GFAP, as well as the values of the MTT test, were similar across all experimental groups.

    “The content of β-III tubulin and GFAP, as well as the values of the MTT test, were similar across all experimental groups.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    DAPT rescued only C83, but not C99 levels, in non-transduced or empty AAV cells.

    “DAPT rescued only C83, but not C99 levels”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    MT5-MMP deficiency in 5xFAD mice prevents glial reactivity and the increase in the levels of pro-inflammatory interleukin-1 beta (IL-1β).

    “MT5-MMP deficiency also prevented glial reactivity and the increase in the levels of pro-inflammatory interleukin-1 beta (IL-1β) in 5xFAD mice [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier J-M, et al. 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(1):217–36. source

  • Probably not a substantial claim.

    Premisecitation

    MMP-2 and MMP-9 have been shown to degrade IL-1β, thus likely contributing to the resolution of inflammation under certain circumstances.

    “Two MT5-MMP homologs, MMP-2 and MMP-9 (also known as gelatinases A and B, respectively), have been shown to degrade IL-1β, thus likely contributing to the resolution of inflammation under certain circumstances [41]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Schönbeck U, Mach F, Libby P. Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol. 1998;161(7):3340–6. source

  • Probably not a substantial claim.

    Premisecitation

    MT5-MMP can modulate APP/Aβ metabolism.

    “Knowing that MT5-MMP can modulate APP/Aβ metabolism [13, 17]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier J-M, et al. 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(1):217–36. source
    • cites [17] Baranger K, Bonnet AE, Girard SD, Paumier J-M, García-González L, Elmanaa W, et al. MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro. Front Mol Neurosci. 2017;9. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    Omission of the primary antibody was used as a control and no immunostaining was observed.

    “Omission of the primary antibody was used as control and no immunostaining was observed.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    MT5-MMP deficiency prevents deficits in long-term potentiation (LTP), spatial learning and working memory in 5xFAD mice.

    “concomitant with prevention of deficits in long-term potentiation (LTP), spatial learning and working memory [13, 17].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier J-M, et al. 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(1):217–36. source
    • cites [17] Baranger K, Bonnet AE, Girard SD, Paumier J-M, García-González L, Elmanaa W, et al. MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro. Front Mol Neurosci. 2017;9. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    IL-1β is a major neuroinflammatory mediator highly expressed in Alzheimer's disease following activation of the NLRP3 inflammasome.

    “IL-1β is a major neuroinflammatory mediator, highly expressed in AD following activation of the NLRP3 inflammasome [18–20]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol. 2015;16(3):229–36. source
    • cites [19] Freeman LC, Ting JP-Y. The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem. 2016;136:29–38. source
    • cites [20] Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19(10):610–21. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Immunoblots were represented in separated columns when bands from the same membrane were not adjacent.

    “Note that immunoblots were represented in separated columns when bands from the same membrane were not adjacent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    IL-1β has complex effects on neurons including disruption of synaptic plasticity, promotion of excitotoxicity, and modulation of α- and γ-secretase activities while reducing β-secretase activity and Aβ levels.

    “shows complex and divers effects on neurons including disruption of synaptic plasticity [21], promotion of excitotoxicity [22, 23] and α- and γ-secretase activities, while reducing β-secretase activity [24, 25] and Aβ levels [26, 27].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [21] Tong L, Prieto GA, Kramar EA, Smith ED, Cribbs DH, Lynch G, et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1 via p38 mitogen-activated protein kinase. J Neurosci. 2012;32(49):17714–24. source
    • cites [22] Viviani B, Gardoni F, Bartesaghi S, Corsini E, Facchi A, Galli CL, et al. Interleukin-1β released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J Biol Chem. 2006;281(40):30212–22. source
    • cites [23] Mishra A, Kim HJ, Shin AH, Thayer SA. Synapse loss induced by interleukin-1β requires pre- and post-synaptic mechanisms. J Neuroimmune Pharmacol. 2012;7(3):571–8. source
    • cites [24] Domingues C, da Cruz e Silva OAB, Henriques AG. Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks. Curr Alzheimer Res. 2017;14(8). source
    • cites [25] Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, et al. Interleukin-1β up-regulates TACE to enhance α-cleavage of APP in neurons: resulting decrease in Aβ production. J Neurochem. 2008;104(5):1387–93. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Changes in inflammatory markers in Alzheimer's disease are often associated with the accumulation of Aβ following amyloidogenic processing of APP.

    “Changes in inflammatory markers in AD are often associated with the accumulation of Aβ following amyloidogenic processing of APP [43, 44].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, et al. Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis. 2002;11(2):257–74. source
    • cites [44] Gasic-Milenkovic J, Dukic-Stefanovic S, Deuther-Conrad W, Gärtner U, Münch G. Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon -gamma and « advanced glycation endproducts » in a murine microglia cell line. Eur J Neurosci. 2003;17(4):813–21. source

  • Probably not a substantial claim.

    Premisecitation

    Deficient cleavage of N-cadherin in the PNS was reported as a possible mechanism explaining the lack of inflammatory response to IL-1β injection in MT5-MMP-deficient mice.

    “deficient cleavage of N-cadherin in the PNS was reported as a possible mechanism explaining the lack of inflammatory response to IL-1β injection in MT5-MMP-deficient mice [10]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Folgueras AR, Valdes-Sanchez T, Llano E, Menendez L, Baamonde A, Denlinger BL, et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc Nat Acad Sci. 2009;106(38):16451–6. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No distinction was made between excitatory or inhibitory synaptic currents.

    “We did not make any distinction between excitatory or inhibitory synaptic currents.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The burst in IL-1β concentration detected by ELISA in cell supernatants after treatment likely reflects the addition of recombinant cytokine.

    “The burst in IL-1β concentration detected by ELISA in cell supernatants after treatment likely reflects the addition of recombinant cytokine”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All experimental procedures were conducted in agreement with the authorization for animal experimentation attributed by the French Ministry of Research to the laboratory.

    “All the experimental procedures were conducted in agreement with the authorization for animal experimentation attributed by the French Ministry of Research to the laboratory (research project: APAFIS#23040-2019112708474721 v4).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Overall, MT5-MMP deficiency modulates the expression of Il-1β, Ccl2 and Il-6 while sparing Tnfa.

    “Overall, MT5-MMP deficiency modulates the expression of Il-1β, Ccl2 and Il-6 while sparing that of Tnfa, which is otherwise unaffected by genotypes or 10 ng/mL IL-1β treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The purity of each subcellular fraction was analyzed by western blot using antibodies against GAPDH, Na+/K+ ATPase and Histone 3 for cytoplasmic, membranous and nuclear fractions, respectively.

    “The purity of each fraction was analyzed by western blot as described above, using antibodies against GAPDH, Na+/K+ ATPase and Histone 3 for cytoplasmic, membranous and nuclear fractions, respectively.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    There is no functional crosstalk between IL-1β and APP/Aβ, and their levels are independently controlled by MT5-MMP.

    “suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation

    For each experiment, cDNA samples were analyzed in duplicate and relative gene expression was obtained using the comparative 2−(ΔΔCt) method after normalization to the Gapdh housekeeping gene.

    “For each experiment, cDNA samples were analyzed in duplicate and relative gene expression was obtained using the comparative 2−(ΔΔCt) method after normalization to the Gapdh (Mm99999915_g1) housekeeping gene [32, 33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] García‐González L, Paumier J, Louis L, Pilat D, Bernard A, Stephan D, et al. MT5‐MMP controls APP and β‐CTF/C99 metabolism through proteolytic‐dependent and ‐independent mechanisms relevant for Alzheimer’s disease. FASEB J. 2021;35(7). source
    • cites [33] Paumier J-M, Py NA, García-González L, Bernard A, Stephan D, Louis L, et al. Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking. FASEB J. 2019;33(2):2910–27. source

  • It may state two separate claims as one.

    Interpretationown data

    MT5-MMP deletion tunes down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism.

    “MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Primary neuron/astrocyte cultures from 5xFAD mice model early AD pathogenic events in vivo.
    • Rests on an assumption: The 5xFAD transgene is active in developing neural cells at 11–14 DIV, producing nascent AD pathogenic events.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationreasoning

    MT5-MMP absence in an inflammatory condition might interfere with the activation of alternative degradation pathways in case of impaired proteasome function.

    “However, MT5-MMP absence in an inflammatory condition might interfere with the activation of alternative degradation pathways in case of impaired proteasome function.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Downregulation of MCP-1 in MT5-MMP-deficient cells could dampen the system's ability to recruit microglia/macrophages to the site of inflammation, thereby helping to limit the progression of an exacerbated inflammatory response.

    “Downregulation of MCP-1 in MT5-MMP-deficient cells could dampen the system's ability to recruit microglia/macrophages to the site of inflammation, thereby helping to limit the progression of an exacerbated inflammatory response.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    These data likely reflect extreme lability and/or relatively low production of endogenous C99 in developing neurons.

    “These data likely reflect extreme lability and/or relatively low production of endogenous C99 in developing neurons.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The Thy1 promoter is activated at 4-5 DIV.

    “This is consistent with previous data showing activation of the Thy1 promoter at 4–5 DIV [46]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Sennvik K, Boekhoorn K, Lasrado R, Terwel D, Verhaeghe S, Korr H, et al. Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/ knockout mice. FASEB J. 2007;21(9):2149–61. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Systemic injection of IL-1β does not trigger an inflammatory response in the PNS of adult MT5-MMP-deficient mice.

    “systemic injection of IL-1β did not trigger an inflammatory response in the PNS of adult MT5-MMP-deficient mice [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Folgueras AR, Valdes-Sanchez T, Llano E, Menendez L, Baamonde A, Denlinger BL, et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc Nat Acad Sci. 2009;106(38):16451–6. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The previous study's no astrocytes and fivefold lower cell density could explain a microenvironment that facilitates neuronal vulnerability.

    “In this study, no astrocytes were reported and cell density was fivefold lower than ours, which could explain a microenvironment that facilitates neuronal vulnerability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    MT1-MMP, MMP-9 and MMP-2 are close MT5-MMP homologues involved in the control of APP metabolism and amyloidogenesis.

    “all close MT5-MMP homologues, also involved in the control of APP metabolism and amyloidogenesis [33, 34, 54, 55]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [33] Paumier J-M, Py NA, García-González L, Bernard A, Stephan D, Louis L, et al. Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking. FASEB J. 2019;33(2):2910–27. source
    • cites [34] Py NA, Bonnet AE, Bernard A, Marchalant Y, Charrat E, Checler F, et al. Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer’s disease: evidence for a pro-amyloidogenic role of MT1-MMP. Front Aging Neurosci. 2014;6. source
    • cites [54] Llorente P, Martins S, Sastre I, Aldudo J, Recuero M, Adjaye J, et al. Matrix metalloproteinase 14 mediates APP proteolysis and lysosomal alterations induced by oxidative stress in human neuronal cells. Ox Med Cell Longev. 2020;2020:1–13. source
    • cites [55] Hernandez-Guillamon M, Mawhirt S, Blais S, Montaner J, Neubert TA, Rostagno A, et al. Sequential amyloid-β degradation by the matrix metalloproteases MMP-2 and MMP-9. J Biol Chem. 2015;290(24):15078–91. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    The onset of neuronal hyperexcitability observed in 5xFAD mice may take place during development.

    “it is possible that the onset of neuronal hyperexcitability observed in 5xFAD mice [67, 68] takes place during development”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Siwek ME, Müller R, Henseler C, Trog A, Lundt A, Wormuth C, et al. Altered theta oscillations and aberrant cortical excitatory activity in the 5XFAD model of Alzheimer’s disease. Neural Plast. 2015;2015:781731. source
    • cites [68] Sompol P, Furman JL, Pleiss MM, Kraner SD, Artiushin IA, Batten SR, et al. Calcineurin/NFAT signaling in activated astrocytes drives network hyperexcitability in Aβ-bearing mice. J Neurosci. 2017;37(25):6132–48. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Several studies highlight mechanisms of IL-1β-mediated excitability: NMDA receptor stimulation of Ca2+ influx, inhibition of GABA-evoked currents, or prevention of the inhibitory effect of cannabinoid CB1 receptor on glutamate release.

    “several studies highlight various mechanisms of IL-1β-mediated excitability: NMDA receptor stimulation of Ca2+ influx [64], inhibition of GABA-evoked currents [65] or prevention of the inhibitory effect of cannabinoid CB1 receptor on glutamate release [66].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [64] Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23:8692–700. source
    • cites [65] Wang S, Cheng Q, Malik S, Yang J. Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther. 2000;292(2):497–504. source
    • cites [66] De Chiara V, Motta C, Rossi S, Studer V, Barbieri F, Lauro D, et al. Interleukin-1β alters the sensitivity of cannabinoid CB1 receptors controlling glutamate transmission in the striatum. Neuroscience. 2013;250:232–9. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In MT5-MMP-deficient mice, MT5-MMP deficiency prevents proper N-cadherin processing, eventually disrupting the crosstalk between sensory neurons and mast cells.

    “MT5-MMP-deficient prevented proper N-cadherin processing eventually disrupting the crosstalk between sensory neurons and mast cells [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Folgueras AR, Valdes-Sanchez T, Llano E, Menendez L, Baamonde A, Denlinger BL, et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc Nat Acad Sci. 2009;106(38):16451–6. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Higher IL-1β concentrations (> 200 pg/mL) have the opposite effect to low levels on autophagolysosomal function and inflammation.

    “while higher cytokine concentrations (> 200 pg/mL) have the opposite effect [60, 61].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] François A, Terro F, Janet T, Bilan AR, Paccalin M, Page G. Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease. J Neuroinflammation. 2013;10(1):915. source
    • cites [61] Francois A, Terro F, Quellard N, Fernandez B, Chassaing D, Janet T, et al. Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice. Mol Brain. 2014;7(1):56. source

  • It may state two separate claims as one.

    Premisecitation

    In the brain of 5xFAD mice at 2 months, IL-1β levels are increased along with the onset of Aβ accumulation.

    “and later at 2 months, along with the onset of Aβ accumulation [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Py NA, Bonnet AE, Bernard A, Marchalant Y, Charrat E, Checler F, et al. Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer’s disease: evidence for a pro-amyloidogenic role of MT1-MMP. Front Aging Neurosci. 2014;6. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The prevention of an increase in amplitude in Tg cells by IL-1β could be interpreted as a homeostatic cellular response to the inflammatory burst.

    “which could be interpreted as a homeostatic cellular response to the inflammatory burst.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    The increased frequency observed in all genotypes is consistent with IL-1β acting as a pre-synaptic neuromodulator.

    “which is consistent with the increased frequency we observed in all genotypes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Low levels of IL-1β stimulate autophagolysosomal function and attenuate inflammation in cell cultures.

    “low levels of IL-1β stimulate autophagolysosomal function and attenuate inflammation in cell cultures”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] François A, Terro F, Janet T, Bilan AR, Paccalin M, Page G. Involvement of interleukin-1β in the autophagic process of microglia: relevance to Alzheimer’s disease. J Neuroinflammation. 2013;10(1):915. source
    • cites [61] Francois A, Terro F, Quellard N, Fernandez B, Chassaing D, Janet T, et al. Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice. Mol Brain. 2014;7(1):56. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The apparent lack of toxicity mediated by IL-1β compared to previous studies may be related to different experimental settings used, including concentrations and time of exposure to the cytokine.

    “In addition, the apparent lack of toxicity mediated by IL-1β compared to previous studies [57, 58] may be related to different experimental settings used, including concentrations and time of exposure to the cytokine.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Thornton P, Pinteaux E, Gibson RM, Allan SM, Rothwell NJ. Interleukin-1-induced neurotoxicity is mediated by glia and requires caspase activation and free radical release. J Neurochem. 2006;98(1):258–66. source
    • cites [58] Corbett GT, Roy A, Pahan K. Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense. J Immunol. 2012;189(2):1002–13. source

  • It may state two separate claims as one.

    Interpretationown data

    MT5-MMP deficiency downregulates Aβ40 and Aβ42 levels in developing neural cells in culture, and this trend is not modified by IL-1β after 24 h of incubation.

    “We conclude that MT5-MMP deficiency downregulates Aβ40 and Aβ42 levels in developing neural cells in culture and that this trend is not modified by IL-1β after 24 h of incubation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    IL-1β may act as a pre-synaptic neuromodulator.

    “IL-1β may also act as pre-synaptic neuromodulator [70, 71]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Murray C. Interleukin-1beta inhibits glutamate release in hippocampus of young, but not aged. Rats Neurobiol Aging. 1997;18(3):343–8. source
    • cites [71] Vereker E, O’Donnell E, Lynch MA. The inhibitory effect of interleukin-1β on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J Neurosci. 2000;20(18):6811–9. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Non-catalytic interactions of MT5-MMP promote C99 degradation by the proteasome and, to a lesser extent, by lysosomes.

    “non-catalytic interactions of MT5-MMP promote C99 degradation by the proteasome and, to a lesser extent, by lysosomes [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] García‐González L, Paumier J, Louis L, Pilat D, Bernard A, Stephan D, et al. MT5‐MMP controls APP and β‐CTF/C99 metabolism through proteolytic‐dependent and ‐independent mechanisms relevant for Alzheimer’s disease. FASEB J. 2021;35(7). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Lower levels of IL-1β in MT5-MMP-deficient neurons could help to attenuate the process of neuronal hyperexcitability in the long run.

    “lower levels of IL-1β in MT5-MMP-deficient neurons could help to attenuate this process in the long run.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    IL-1β has diverse and sometimes divergent effects on neuronal activity depending on cell-type, cytokine concentration and duration of the stimulus.

    “IL-1β has diverse and sometimes divergent effects on neuronal activity depending on cell-type, cytokine concentration and duration of the stimulus [63]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70–82. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    A possible post-synaptic mechanism of IL-1β underlying its effect is the cytokine-mediated decrease in the content and phosphorylation of the AMPA-GluR1 subunit at the post-synaptic membrane.

    “A possible post-synaptic mechanism of IL-1β underlying such effect could be the cytokine-mediated decrease in the content and phosphorylation of the AMPA-GluR1 subunit at the post-synaptic membrane [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Lai AY, Swayze RD, El-Husseini A, Song C. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J Neuroimmunol. 2006;175(1–2):97–106. source

  • It may state two separate claims as one.

    Interpretationown data

    The Thy1 neuronal promoter was functional to drive human transgene expression and efficient metabolization of human APP.

    “indicating that the Thy1 neuronal promoter was functional to drive human transgene expression and efficient metabolization of human APP.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    C83 is a preferential substrate of γ-secretase and the most abundant APP fragment in cultured neurons.

    “consistent with C83 being a preferential substrate of γ-secretase [32] and the most abundant APP fragment in cultured neurons [15, 16]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] García‐González L, Paumier J, Louis L, Pilat D, Bernard A, Stephan D, et al. MT5‐MMP controls APP and β‐CTF/C99 metabolism through proteolytic‐dependent and ‐independent mechanisms relevant for Alzheimer’s disease. FASEB J. 2021;35(7). source
    • cites [15] Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, et al. Defective transcytosis of APP and lipoproteins in human iPSC-derived neurons with familial Alzheimer’s disease mutations. Cell Rep. 2016;17(3):759–73. source
    • cites [16] Tan JZA, Gleeson PA. The trans-Golgi network is a major site for alpha-secretase processing of amyloid precursor protein in primary neurons. J Biol Chem. 2019;294(5):1618–31. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationown data

    It cannot be excluded that a small functional pool of the WB-undetectable sAPP fragment reaches the synapse.

    “we cannot exclude that a small functional pool of this WB-undetectable fragment reaches the synapse.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Modulation of MT5-MMP has possible therapeutic implications in AD.

    “further enhancing interest in this proteinase and the possible therapeutic implications of its modulation in AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The complexity of the effects of IL-1β must consider the limitations of the experimental setting, including the use of a single concentration of IL-1β.

    “the complexity of the effects (or lack thereof) of the cytokine must consider the limitations of our experimental setting, including for example the use of a single concentration of IL-1ß.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    All or some of the mechanisms of C99 clearance (low pace formation, proteasomal/autophagolysosomal degradation, α-secretase cleavage) are active in developing neural cells, thus preventing the neurotoxic effects of C99 accumulation.

    “Likely, all or some of these mechanisms are active in developing neural cells, thus preventing the neurotoxic effects of C99 accumulation [29, 45, 75].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Lauritzen I, Pardossi-Piquard R, Bourgeois A, Pagnotta S, Biferi MG, Barkats M, et al. Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology. Acta Neuropathol. 2016;132(2):257–76. source
    • cites [45] Lauritzen I, Pardossi-Piquard R, Bauer C, Brigham E, Abraham JD, Ranaldi S, et al. The beta-secretase-derived C-terminal fragment of betaAPP, C99, but not Abeta, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci. 2012;32(46):16243–55. source
    • cites [75] Vaillant-Beuchot L, Mary A, Pardossi-Piquard R, Bourgeois A, Lauritzen I, Eysert F, et al. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains. Acta Neuropathol. 2021;141(1):39–65. source
    • The authors state this as an assumption: C99 is formed at a low pace and/or promptly degraded by the proteasome or autophagolysosome, and even by α-secretase to yield C83.

  • It may state two separate claims as one.

    Interpretationreasoning

    Inflammation and neuronal activity are important early markers of pathology onset in AD settings.

    “suggesting that they are important early markers of pathology onset in AD settings.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    The reduction in neprilysin could underlie a negative feedback response to a potential increase in neprilysin activity.

    “unless it actually underlies a negative feedback response to a potential increase in neprilysin activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    No general conclusion can be drawn from the correlation between capacitance and gPSCs because this correlation was not validated in the other experimental groups.

    “However, no general conclusion can be drawn, as this correlation was not validated in the other experimental groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    The lack of MT5-MMP could prevent the formation of sAPP95/sAPPη.

    “Alternatively, the lack of MT5-MMP could prevent the formation of sAPP95/sAPPη, recently suggested to bind the GABABR1a and inhibit pre-synaptic neurotransmitter release [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Rice HC, de Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN, et al. Secreted amyloid-beta precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science. 2019;363(6423). source

  • It may state two separate claims as one.

    Interpretationown data

    MT5-MMP deficiency appears to prevent AD genotype-related synaptic dysfunction under basal conditions, while exacerbating IL-1β-induced neuronal excitability.

    “MT5-MMP deficiency appears to prevent AD genotype-related synaptic dysfunction under basal conditions, while exacerbating IL-1β-induced neuronal excitability.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    MT5-MMP could differentially affect various IL-1β signaling pathways mediated or not by membrane receptors.

    “raising the possibility that MT5-MMP could differentially affect various IL-1β signaling pathways mediated [63] or not [72] by membrane receptors.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70–82. source
    • cites [72] Cebo C, Dambrouck T, Maes E, Laden C, Strecker G, Michalski J-C, et al. Recombinant human interleukins IL-1α, IL-1β, IL-4, IL-6, and IL-7 show different and specific calcium-independent carbohydrate-binding properties. J Biol Chem. 2001;276(8):5685–91. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Murine Aβ implicitly proved the formation at some point of its immediate precursor, C99.

    “murine Aβ implicitly proved the formation at some point of its immediate precursor, C99.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The increase in capacitance correlates with the increase in membrane surface area and pre-synaptic vesicle fusion.

    “as the increase in capacitance correlates with the increase in membrane surface area and pre-synaptic vesicle fusion [69]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Lai AY, Swayze RD, El-Husseini A, Song C. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J Neuroimmunol. 2006;175(1–2):97–106. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    A parallelism could be established between the increase in capacitance and the observation of increased gPSCs and capacitance in IL-1β-treated MT5−/− neurons.

    “a parallelism could be established with the observation of increased gPSCs and capacitance in IL-1β-treated MT5−/− neurons.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Young neurons have the potential to prevent the accumulation of endogenous C99 and thus prevent the derived detrimental consequences.

    “young neurons have the potential to prevent the accumulation of endogenous C99 and thus prevent the derived detrimental consequences.”
    Quote in the paperNot a substantial claim
85 of 85

  • The paper relies on this without support.

    Primary neuron/astrocyte cultures from 5xFAD mice model early AD pathogenic events in vivo.

    “We tested these hypotheses using mixed neuron/astrocyte primary cortical cultures from wild type (WT), 5xFAD (Tg), MT5-MMP−/− (MT5−/−) and 5xFAD/MT5-MMP−/− (TgMT5−/−) mice [13, 17] stimulated or not by IL-1β.”

  • The paper relies on this without support.

    The 5xFAD transgene is active in developing neural cells at 11–14 DIV, producing nascent AD pathogenic events.

    “It was also our objective to explore the possibility that such modulations occur in young neural cells of 5xFAD brains, well before the first pathological signs.”

  • The paper relies on this without support.

    Aβ content results from a balance between production and degradation.

    “Because Aβ content results from a balance between production and degradation”

  • The paper relies on this without support.

    Primary cortical cultures from 5xFAD mice at 11 DIV model early AD pathogenesis.

    “This confirms the beneficial effect of MT5-MMP modulation on the early cellular dysfunctions identified, which are likely precursors to the pathogenesis of AD.”

  • The paper relies on this without support.

    IL-1β treatment at 10 ng/mL for 24 h mimics neuroinflammation relevant to AD.

    “neuroinflammation caused by IL-1β treatment did not impact the levels of APP metabolites (e.g., Aβ and APP CTFs), which were instead controlled by the presence or absence of MT5-MMP.”

  • The paper relies on this without support.

    C99 accumulation is a major pathogenic feature of AD.

    “We conclude that MT5-MMP deficiency effectively prevents the accumulation of C99, a major pathogenic feature of AD and, more interestingly, that this can occur in developing neural cells.”

  • The paper relies on this without support.

    The AAV-C99 overexpression model reflects endogenous C99 metabolism in developing neurons.

    “To circumvent this difficulty and assess whether MT5-MMP could actually regulate C99 levels in developing neurons, we overexpressed human C99 in WT and MT5−/− cultures using an AAV-C99 under the control of the neuron-specific synapsin promoter [29].”

  • The authors state this as an assumption.

    C99 is formed at a low pace and/or promptly degraded by the proteasome or autophagolysosome, and even by α-secretase to yield C83.

    “We assume that the latter is formed at a low pace and/or that it is promptly degraded by the proteasome or autophagolysosome [32], and even by α-secretase to yield C83 [32, 74].”
8 of 8

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Metadata

Authors
Pilat, D., Paumier, J.-M., García-González, L., Louis, L., Stephan, D., Manrique, C., Khrestchatisky, M., Di Pasquale, E., Baranger, K., & Rivera, S.
Affiliations
  • Northwestern University (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Baranger, Kévin
  • Rivera, Santiago
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2022-03-11
Volume
19
Issue
1
Pages
65-65
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-022-02407-z
PMC
PMC8915472
OpenAlex
W4220714003
Cited by
28
References
78
Citations by year
2026: 6 · 2025: 5 · 2024: 11 · 2023: 4 · 2022: 2
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • aix-marseille université
  • centre national de la recherche scientifique
  • agence nationale de la recherche (MAD5, ANR-17-EURE-0029)
  • centre of excellence in neurodegeneration (ADMIRE-MT5)
  • fondation pour la recherche médicale (ALZ201912009627, FDT202001011017, FDT201904008423)
  • fondation plan alzheimer (ALZ201912009627)
  • fondation vaincre alzheimer
  • excellence initiative of aix-marseille university-a*midex (Management of Talents)
  • initiative d’excellence d’aix-marseille université via a*midex (AMX-19-IET-004)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
Alzheimer's disease, 5xFAD mice, neuroinflammation, neuronal excitability, amyloid-beta, IL-1β, APP processing, C99, astrocytes, neurons, amyloidosis, synaptic activity, cognitive impairment, AAV gene delivery
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Matrix Metalloproteinases, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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