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Cited by 89Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 222 of the 225 references it cites were found in a registry or an index; 8 of the 237 sources its claims cite were checked for support.

Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

Open access
García-González, Laura, Pilat, Dominika, Baranger, Kévin, Rivera, Santiago·2019·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2019.00244PMC PMC6769103
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Abstract

Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (Aβ) by β-secretase and γ-secretase complex is at the heart of the pathogenesis of Alzheimer's disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of β- and γ-secretases as targets, new APP-cleaving enzymes, including meprin-β, legumain (δ-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/η-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology. This review will discuss recent findings on the roles of all these proteinases in the nervous system, and in particular on the roles of MT-MMPs, which are at the crossroads of pathological events involving not only amyloidogenesis, but also inflammation and synaptic dysfunctions. Assessing the potential of these emerging proteinases in the Alzheimer's field opens up new research prospects to improve our knowledge of fundamental mechanisms of the disease and help us establish new therapeutic strategies.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that APP proteolysis remains central to Alzheimer’s disease pathogenesis and highlights emerging APP-cleaving proteinases, especially MT1-MMP and MT5-MMP, as modulators of amyloidogenesis, inflammation, and synaptic dysfunction. It synthesizes evidence that MT5-MMP/η-secretase and MT1-MMP can promote amyloidogenic APP processing while also showing Aβ-degrading or BACE-1-surrogate activities.

Key findings

  • Canonical β- and γ-secretase targeting has failed clinically, but new APP-cleaving enzymes—meprin-β, legumain/δ-secretase, RHBDL4, caspases, and MT-MMPs/η-secretases—support APP processing as a continuing AD mechanism. Meprin-β can cleave at the β-site and generate Aβ2–X; legumain cleaves APP at positions 373 and 585 (APP695 numbering), producing APP1–373 and APP586–695; RHBDL4 decreases Aβ38, Aβ40, and Aβ42; caspases cleave APP mainly between V664–D665 in the intracytoplasmic domain.
  • MT5-MMP was identified as an η-secretase cleaving APP at VLAN504–M505ISEPR (APP695 numbering), generating sAPPη/sAPP95 and η-CTF/CTF-30. In 5xFAD/MT5–/– mice, soluble Aβ40 and Aβ42, oligomers, plaques, and C99 were strikingly lower, with fewer reactive microglia/astrocytes, reduced IL-1β and TNF-α, and prevention of LTP and spatial/working memory deficits; some benefits persisted at 16 months.
  • MT1-MMP can cleave APP and degrade Aβ, but in HEKswe cells it also increases Aβ, sAPP95, CTF-30, and C99; about 50% of sAPP95 release is estimated to involve MMP-2. MT1-MMP can restore basal Aβ levels when BACE-1 is inhibited, suggesting a possible surrogate β-secretase role, and MT1-MMP is upregulated in cortex and hippocampus of 6-month-old 5xFAD mice.
  • TIMPs regulate MT-MMPs: TIMP-2, -3, and -4 inhibit MT1-MMP, while MT5-MMP is targeted only by TIMP-2; TIMP-1 is a very poor inhibitor of MT-MMPs. Clinical TIMP-2 data in AD are inconsistent, with no change, no difference, or increased levels reported across studies.

Methods

  • Design: narrative review, not a primary experimental study.
  • Data or sample: published literature on APP metabolism, secretases, emerging proteinases, MT-MMPs, TIMPs, and AD models; no new human or animal sample was collected.
  • Main analysis: qualitative synthesis of cited in vitro, mouse-model, human biomarker/postmortem, and inhibitor studies, organized around APP cleavage sites, emerging APP-processing enzymes, MT1-/MT5-MMP biology, and therapeutic implications.

Limitations

  • Stated by the paper: many findings remain correlative or speculative; in vivo validation is needed for MT1-MMP and RHBDL4; the exact nature of sAPP95 remains to be established; functional evidence for MT5-MMP/γ-secretase interaction is lacking; studies on TIMP regulation of ADAMs in AD are lacking; substrate lists for emerging proteinases may grow.
  • Evident from the text: as a review, it provides no systematic search, meta-analysis, or new data, and conclusions depend on cited cell-line, mouse-model, and human observational studies, some with inconsistent clinical inhibitor findings.

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

Integrity signals

Registry

Crossref · 10.3389/fnagi.2019.00244

Cites

222 of 223 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

8 of 237 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Legumain deficiency in the 5xFAD transgenic mouse model of AD causes a drop in Aβ40, Aβ42, and amyloid plaque burden.

    “legumain deficiency in the 5xFAD transgenic mouse model of AD (Oakley et al., 2006) causes a drop of Aβ40, Aβ42 and amyloid plaque burden”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Oakley et al., 2006 source
    • cites Zhang et al., 2015 source
    • Rests on an assumption: Findings from mouse models and cultured cells about meprin-β and legumain APP processing can be extrapolated to human AD pathogenesis.
  • Premisecitation

    Plasma of young TIMP-2 knockout mice failed to rescue the aged phenotype.

    “the plasma of young TIMP-2 knockout mice failed to rescue the aged phenotype.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Castellano et al., 2017 source

      The paper reports that TIMP2 is absent from young knockout mouse plasma and that TIMP2-depleted human cord plasma loses cognitive benefits in aged mice (Abstract; page unavailable). It does not report giving plasma from young TIMP2 knockout mice to aged mice or testing whether that plasma rescues an aged phenotype. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Aβ results from proteolysis of APP.

    “Aβ results from the proteolysis of APP, a type I transmembrane protein targeted first at the plasma membrane, then rapidly endocytosed to endosomes to be metabolized to Aβ or subsequently sent to the lysosomal compartment for degradation (Wang X. et al., 2017; Van Acker et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wang X. et al., 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Van Acker et al., 2019 source
  • Premisecitation

    BACE-1 can cleave Aβ40 or Aβ42 to generate a C-terminal truncated Aβ34 form.

    “More recently, it has been shown that BACE-1 can also cleave Aβ40 or Aβ42 to generate a C-terminal truncated Aβ34 form”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liebsch et al., 2019 source
  • Interpretationcitation

    A causal effect between β'-cleavage and neuroprotection is not straightforward because Aβ11-40 is found in insoluble Aβ pools of post-mortem AD brains.

    “However, a causal effect between β’-cleavage and neuroprotection is not straight forward as Aβ11–40 is found in insoluble Aβ pools of post-mortem AD brains (Huse et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Huse et al., 2002 source
  • Probably not a substantial claim. 31
  • It may state two separate claims as one. 58
  • The quote only partly states this claim. 1

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

    Premisecitation

    BACE-1 cleaves numerous substrates, conferring a wide spectrum of physiological and pathological activities.

    “BACE-1 cleaves numerous substrates, which confers this enzyme a wide spectrum of physiological and pathological activities (Kuhn et al., 2012; Zhou et al., 2012; Vassar et al., 2014), but it is indisputably its ability to process APP that has attracted much attention, especially in relation to AD.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Kuhn et al., 2012 source

      The Identification of neuronal BACE1 sheddome section reports 34 neuronal membrane proteins whose shedding depends on BACE1. The Introduction links APP cleavage to pathogenic amyloid production and neuregulin-1 cleavage to myelination. But the Discussion says the functional consequences of cleavage remain unknown for most substrates, so the claim that cleavage confers a wide spectrum of physiological and pathological activities is stronger than the paper establishes. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Zhou et al., 2012 source
    • cites Vassar et al., 2014 source

  • It may state two separate claims as one.

    Interpretationcitation

    Aβ neurotoxicity probably reflects a combination of events triggered by Aβ accumulation, including Tau hyperphosphorylation and NFT formation, inflammation, and synaptic dysfunction.

    “probably reflecting a combination of events triggered by its accumulation, including stimulation of Tau hyperphosphorylation and subsequent formation of neurofibrillary tangles (NFTs), promotion of inflammation and also synaptic dysfunctions”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Benilova et al., 2012 source
    • cites Mucke and Selkoe, 2012 source

      The paper’s discussion of elevated Aβ and synaptic transmission reports synaptic impairment and loss. Its introductory section also says nonneuronal changes, including microgliosis and astrocytosis, may contribute to neuronal dysfunction. The paper does not establish the claimed sequence from Aβ-induced tau hyperphosphorylation to neurofibrillary tangle formation; tau hyperphosphorylation appears in the title of a work listed in its References, but that does not support the full sequence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Selkoe and Hardy, 2016 source

  • It may state two separate claims as one.

    Premisecitation

    sAPPα interacts with BACE-1 and inhibits Aβ production.

    “sAPPα interacts with BACE-1 and inhibits Aβ production”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Obregon et al., 2012 source

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

    Premisecitation

    Tau can cause APP-dependent impairment of LTP and spatial learning in mice.

    “also Tau could cause APP-dependent impairment of LTP and spatial learning in mice (Puzzo et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Puzzo et al., 2017 source

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

    Premisecitation

    Endosomes are thought to be the main locus of Aβ production, which is ensured by canonical β- and γ-secretases.

    “Endosomes are thought to be the main locus of Aβ production, which is ensured by canonical β- and γ-secretases (Vassar et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vassar et al., 1999 source

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

    Premisecitation

    BACE-1 requires an acidic environment (optimum pH 4.5) to be enzymatically active.

    “This type I transmembrane protein of the aspartyl proteinase family needs an acidic environment (optimum pH 4.5) to be enzymatically active (Saric et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Saric et al., 2013 source

  • It may state two separate claims as one.

    Premisecitation

    Aβ34 appears to be a new biomarker of Aβ clearance in AD, being noticeably increased in mild cognitive impaired patients along with strong BACE-1 activity.

    “which appears to be a new biomarker of Aβ clearance in AD as it is noticeably increased in mild cognitive impaired patients along with strong BACE-1 activity (Liebsch et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liebsch et al., 2019 source

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

    Premisecitation

    Matrix metalloproteinases including MMP-2, MMP-3, MMP-7 and MMP-9 also cleave within the Aβ sequence.

    “Matrix metalloproteinases (MMPs), including MMP-2, MMP-3, MMP-7 and MMP-9 also cleave within the Aβ sequence (Rivera et al., 2019) and these cleavages have been compared to those of membrane-type MMPs (MT-MMPs) in Figure 1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rivera et al., 2019 source

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

    Premisecitation

    The γ-secretase complex is formed by a PS1 or PS2 catalytic subunit and three partner proteins, Aph-1, pen-2 and nicastrin.

    “The γ-secretase complex is formed by a PS1 or PS2 catalytic subunit and 3 partner proteins, Aph-1, pen-2 and nicastrin (Haass et al., 2012; Rajendran and Annaert, 2012; Masters et al., 2015; Selkoe and Hardy, 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Haass et al., 2012 source
    • cites Rajendran and Annaert, 2012 source
    • cites Masters et al., 2015 source

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

    Premisecitation

    Physiologically relevant Aβ degradation is mainly attributed to four metalloproteinases: neprilysin, insulin degrading enzyme, endothelin converting enzyme and angiotensin converting enzyme.

    “Physiologically relevant Aβ degradation has been mainly attributed to 4 metalloproteinases: neprilysin, insulin degrading enzyme, endothelin converting enzyme and angiotensin converting enzyme, the regulation and functions of which have been extensively reviewed elsewhere (De Strooper, 2010; Nalivaeva et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites De Strooper, 2010 source
    • cites Nalivaeva et al., 2012 source

  • It may state two separate claims as one.

    Premisecitation

    β'-cleavage is favored in the neuroprotective Icelandic APP mutation while canonical β-cleavage at Asp1 is reduced.

    “Interestingly, β’-cleavage is favored in the neuroprotective Icelandic APP mutation while the canonic β-cleavage at Asp1 is reduced (Kimura et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kimura et al., 2016 source

  • It may state two separate claims as one.

    Interpretationcitation

    BACE-1 is a prominent Aβ-generating enzyme but also an occasional Aβ-degrading enzyme under some circumstances.

    “Together, these data confirm early studies (Fluhrer et al., 2003; Shi et al., 2003), placing BACE-1 as a prominent Aβ-generating, but also as an occasional Aβ-“degrading” enzyme under some circumstances.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fluhrer et al., 2003 source
    • cites Shi et al., 2003 source

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

    Premisecitation

    The subcellular location and substrate specificity of γ-secretase may vary depending on the presence of PS1 or PS2 in the complex.

    “The subcellular location and substrate specificity of γ-secretase may vary depending on the presence of PS1 or PS2 in the complex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sannerud et al., 2016 source

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

    Premisecitation

    γ-secretase targets many substrates in addition to APP, with consequent impact on a vast array of physiological and pathological processes.

    “Like BACE-1, γ-secretase targets many substrates in addition to APP, with the consequent impact on a vast array of physiological and pathological processes (Haapasalo and Kovacs, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Haapasalo and Kovacs, 2011 source

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

    Premisecitation

    sAPPα acts as a ligand of GABABR1a.

    “sAPPα has been shown to act as a ligand of GABABR1a”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rice et al., 2019 source

  • It may state two separate claims as one.

    Interpretationreasoning

    TIMP-1 could contribute to AD neuroinflammation and/or downregulate ADAM10 activity.

    “suggesting altogether that TIMP-1 could contribute to AD neuroinflammation and/or downregulate ADAM10 activity”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Aβ has antimicrobial activities.

    “a few studies indicate that Aβ has antimicrobial activities”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Soscia et al., 2010 source
    • cites Moir et al., 2018 source
    • cites Dominy et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    AICD is a signaling molecule that can translocate to the nucleus and regulate expression of manifold genes, some involved in AD pathogenic mechanisms, cytoskeleton dynamics, cell cycle control, or synaptic plasticity.

    “AICD has gained consensus as signaling molecule that can translocate to the nucleus and regulate the expression of manifold genes, some of them involved in AD pathogenic mechanisms (Kim et al., 2003; Chang et al., 2006), but also in cytoskeleton dynamics, cell cycle control or synaptic plasticity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kim et al., 2003 source
    • cites Chang et al., 2006 source

  • It may state two separate claims as one.

    Premisecitation

    TIMP-3 reduces α-cleavage of APP and the cell surface levels of ADAM10 and APP in neuroblastoma cells, leading to increased endocytosis and β-secretase cleavage.

    “this inhibitor not only reduces α-cleavage of APP but also the cell surface levels of ADAM10 and APP, which leads to increased endocytosis and β-secretase cleavage”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoe et al., 2007 source

  • It may state two separate claims as one.

    Premisecitation

    Moderate neuronal overexpression of ADAM10 in transgenic AD mice increased sAPPα levels and decreased Aβ, with reduction of deficits in long-term potentiation and learning.

    “These data linking sAPPα to neuroprotection were later confirmed by studies showing that moderate neuronal overexpression of ADAM10 in transgenic AD mice favored an increase in sAPPα levels and a decrease in Aβ, concomitant with a reduction of deficits in long-term potentiation (LTP) and learning (Postina et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Postina et al., 2004 source

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

    Interpretationreasoning

    Studies are lacking to confirm or refute whether a regulatory action of TIMPs on ADAMs impacts AD progression.

    “Clearly, studies are lacking to confirm or refute the idea that a regulatory action of TIMPs on ADAMs could impact on the progression of the disease.”
    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

    α-secretase cleavage of APP is performed by ADAMs of the metzincin superfamily, constitutively by ADAM10 or in a regulated manner by ADAM17/TACE.

    “This is performed by a disintegrin and metalloproteinases (ADAMs) of the metzincin superfamily of metalloproteinases (Rivera et al., 2010; Paschkowsky et al., 2019), in a constitutive (ADAM10) or regulated manner (ADAM17; also known as TACE for TNF-α converting enzyme) (Lammich et al., 1999; Jorissen et al., 2010; Kuhn et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rivera et al., 2010 source
    • cites Paschkowsky et al., 2019 source
    • cites Lammich et al., 1999 source

  • It may state two separate claims as one.

    Premisecitation

    Aβ oligomers may be responsible for sAPPα release by cultured neurons and also in vivo.

    “Aβ oligomers may be responsible for sAPPα release by cultured neurons and also in vivo”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rose et al., 2018 source

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

    Premisecitation

    Presenilins are acidic proteinases with an optimum pH of 6.3.

    “Presenilins are acidic proteinases [optimum pH 6.3, (Campbell et al., 2003)] that belong to the family of seven transmembrane domain proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Campbell et al., 2003 source

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

    Premisecitation

    In 5xFAD mice, TIMP-3 mRNA levels show mild variations at different ages compared with wild type.

    “another study in 5xFAD mice, showed mild variations of TIMP-3 mRNA levels at different ages, compared to wild type (Py et al., 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Py et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Aβ inhibits ADAM10 in mouse primary neuronal cultures, thus favoring endogenous APP processing by β-secretase.

    “Aβ inhibits ADAM10 in mouse primary neuronal cultures, thus favoring endogenous APP processing by β-secretase (Spilman et al., 2016)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Spilman et al., 2016 source

  • It may state two separate claims as one.

    Premisecitation

    sAPPβ induces axonal pruning but not neuronal death, and interacts with DR6 through the C-terminal E2 domain above the β-cleavage site.

    “instead sAPPβ was reported to induce axonal pruning but not neuronal death, and to interact with DR6 through the more C-terminal E2 domain placed above the β-cleavage site (Olsen et al., 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Olsen et al., 2014 source

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

    Premisecitation

    The PS1-containing γ-secretase complex is widely distributed in the cell, whereas a single acidic-dileucine sorting motif in PS2 directs the complex to late endosomes/lysosomes.

    “While the complex containing PS1 is widely distributed in the cell, a single acidic-dileucine sorting motif present in PS2 directs the γ-secretase complex to late endosomes/lysosomes (Sannerud et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sannerud et al., 2016 source

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

    Premisecitation

    AICD can be translocated in the nucleus and engages in transcriptional activities, which are to some extent still controversial in the AD field.

    “The latter can be translocated in the nucleus and engages in transcriptional activities, which are to some extent still controversial in the AD field (reviewed in Pardossi-Piquard and Checler, 2012) (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pardossi-Piquard and Checler, 2012 source

  • It may state two separate claims as one.

    Premisecitation

    TIMP-3 levels are elevated in 3xTg transgenic mouse neurons and in AD brain homogenates.

    “elevated neuronal immunostaining found in 3xTg transgenic mouse and by increased levels in AD brain homogenates (Hoe et al., 2007)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hoe et al., 2007 source

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

    Premisecitation

    A recent review identified nearly 40 genes targeted by AICD in relation to AD pathogenic mechanisms, cytoskeleton dynamics, cell cycle control, synaptic plasticity, and other processes.

    “A recent review has identified nearly 40 genes targeted by the AICD in relation with these and other processes (Bukhari et al., 2017)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bukhari et al., 2017 source

  • It may state two separate claims as one.

    Premisecitation

    TIMP-1 expression is highly upregulated in the brain of transgenic 5xFAD mice at early stages of the pathology and remains durably high.

    “TIMP-1 expression is highly upregulated in the brain of transgenic 5xFAD mice at early stages of the pathology and remains durably high”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Py et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one. The quote only partly states this claim.

    Interpretationcitation

    The potential relevance of TIMP-3 in promoting AD pathogenesis is reinforced by elevated neuronal immunostaining in 3xTg mice and increased TIMP-3 levels in AD brain homogenates.

    “The potential relevance of TIMP-3 in promoting AD pathogenesis is reinforced in this study by the elevated neuronal immunostaining”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoe et al., 2007 source

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

    Premisecitation

    Legumain is involved in numerous pathological settings, including atherosclerosis, osteoporosis, cancer, ischemic stroke, and neurodegenerative diseases.

    “legumain has been involved in numerous pathological settings, including atherosclerosis, osteoporosis, cancer, ischemic stroke, and neurodegenerative diseases (Lunde et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lunde et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    Legumain is a Tau- or APP-cleaving enzyme.

    “and as a Tau- or APP-cleaving enzyme (Zhang et al., 2014, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhang et al., 2014 source
    • cites Zhang et al., 2015 source

  • It may state two separate claims as one.

    Premisecitation

    Picomolar concentrations of Aβ are sufficient to stimulate nicotinic receptors and subsequently LTP and learning and memory in healthy rodents.

    “picomolar concentrations of Aβ are sufficient to stimulate nicotinic receptors and subsequently LTP and learning and memory in healthy rodents (Puzzo et al., 2008, 2012; Morley et al., 2010)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Puzzo et al., 2008 source
    • cites Puzzo et al., 2012 source
    • cites Morley et al., 2010 source

  • It may state two separate claims as one.

    Premisecitation

    Meprin-β preferentially generates Aβ1-40 and an N-terminally truncated Aβ (Aβ2-X).

    “and preferentially generates Aβ1–40 and a N-terminally truncated Aβ (Aβ2–X)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bien et al., 2012 source

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

    Premisecitation

    Legumain is a soluble cysteine proteinase mainly found in endo-lysosomal compartments that provide the optimal functional pH of 6.

    “Legumain, also known as asparagine endopeptidase, is a soluble cysteine proteinase mainly found in endo-lysosomal compartments that provide the optimal functional pH of 6.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen et al., 1997 source
    • cites Alvarez-Fernandez et al., 1999 source

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

    Interpretationreasoning

    Disruptions of physiological functions of APP could alter the subcellular location of APP and thereby the degree of pathogenicity of proteolytic fragments depending on whether they are mainly generated in endosomes or in the cell membrane.

    “it could also alter the subcellular location of APP and thus the degree of pathogenicity of proteolytic fragments depending on whether they are mainly generated in endosomes (e.g., C99, Aβ) or in the cell membrane (e.g., sAPPα).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Aβ oligomers and Tau cause APP-dependent impairment of LTP and spatial learning in mice.

    “Aβ oligomers and also Tau could cause APP-dependent impairment of LTP and spatial learning in mice (Puzzo et al., 2017)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Puzzo et al., 2017 source

  • It may state two separate claims as one.

    Premisecitation

    Legumain cleaves APP at positions 373 and 585 (APP695 numbering), generating two fragments with distinctive cytotoxicity.

    “legumain can cleave APP at positions 373 and 585 (APP695 numbering), generating 2 fragments with distinctive cytotoxicity (Zhang et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2015 source

  • It may state two separate claims as one.

    Premisecitation

    In vitro, meprin-β cleaves APP at the β-cleavage site and after the first and second amino acids of the Aβ sequence.

    “Using a synthetic peptide mimicking APP/Aβ sequence, it was shown in vitro that meprin-β was able to cleave APP at the β-cleavage site and after the first and second amino acids of the Aβ sequence”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bien et al., 2012 source

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

    Premisecitation

    Meprin-β is a type I transmembrane protein of the astacin group of the metzincin superfamily of metalloproteinases.

    “Meprin-β is a type I transmembrane protein of the astacin group of the metzincin superfamily of metalloproteinases (Villa et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Villa et al., 2003 source

  • It may state two separate claims as one.

    Premisecitation

    Cultured hippocampal neurons with truncated APP gene accumulate APP on the plasma membrane and present reduced colocalization of BACE-1 and APP in endosomes, confirming a key role of the YENPTY sequence in APP internalization and Aβ production by endosomes.

    “In addition, it was shown that cultured hippocampal neurons with truncated APP gene accumulate APP on the plasma membrane and present reduced colocalization of BACE-1 and APP in endosomes, confirming a key role of the YENPTY sequence in APP internalization and Aβ production by endosomes (Sun et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sun et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    Decreased APP processing and amyloidogenesis upon MT5-MMP deficiency were concomitant with fewer reactive microglial cells and astrocytes around amyloid plaques, as well as reduced levels of IL-1β and TNF-α.

    “Moreover, decreased APP processing and amyloidogenesis upon MT5-MMP deficiency were concomitant with fewer reactive microglial cells and astrocytes around amyloid plaques, as well as reduced levels of IL-1β and TNF-α (Baranger et al., 2016b, 2017a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baranger et al., 2016b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Baranger et al., 2017a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationcitation

    Aη-γ peptides were not detected, probably revealing a lack of functional interaction between η- and γ-secretase.

    “Aη-γ peptides, potentially generated by a combined action of MT5-MMP and γ-secretase, were not detected, probably revealing a lack of functional interaction between η- and γ-secretase as it is the case with BACE-1, ADAM10 and γ-secretase (Chen et al., 2015; Liu et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen et al., 2015 source
    • cites Liu et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    sAPP95/sAPPη binds GABABR1a, which also acts as a receptor for sAPPα and sAPPβ, resulting in a reduced probability of presynaptic release.

    “The function of sAPP95/sAPPη is not yet known, but a recent study showed that it binds GABABR1a, which also acts as a receptor for sAPPα and sAPPβ, resulting in a reduced probability of presynaptic release (Rice et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rice et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    When γ-secretase processes C99 into Aβ, the remaining AICD is further cleaved by caspase to generate C31 and JCasp fragments, both of which promote neuronal apoptosis.

    “When γ-secretase processes C99 into Aβ, the remaining AICD is further cleaved by caspase to generate C31 and JCasp fragments, both of which promote neuronal apoptosis (Bertrand et al., 2001; Madeira et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bertrand et al., 2001 source
    • cites Madeira et al., 2005 source

  • It may state two separate claims as one.

    Premisereasoning

    Aβ levels remained stable in HEK293 cells expressing MT3-MMP, probably indicating that MT3-MMP processes APP in cell compartments that do not influence amyloidogenesis.

    “Despite this, Aβ levels remained stable in HEK293 cells expressing MT3-MMP, probably indicating that MT3-MMP processes APP in cell compartments that do not influence amyloidogenesis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Cleavage of APP by caspases generates a membrane-bound N-terminal fragment named APP-Ncas and an intracellular C-terminal peptide of 31 amino acids named APP-Ccas or C31.

    “Cleavage of APP by caspases generates a membrane bound N-terminal fragment, named APP-Ncas, and an intracellular C-terminal peptide of 31 amino acids, named APP-Ccas or C31.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The release of sAPP95 by MT1-MMP does not involve BACE-1, but may involve MMP-2.

    “Although functional interactions between MT1-MMP and APP/Aβ are not fully understood, it has been shown that the release of sAPP95 by MT1-MMP does not involve BACE-1, but it may involve MMP-2.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Compared to 5xFAD, 5xFAD/MT5-/- mice showed significantly lower levels of sAPP95, validating in vitro observations and APP being an in vivo physiological substrate of MT5-MMP.

    “Compared to 5xFAD, 5xFAD/MT5–/– mice showed significantly lower levels of sAPP95, validating our in vitro observations and APP being an in vivo physiological substrate of MT5-MMP (Baranger et al., 2016b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baranger et al., 2016b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Aη-α and Aη-β peptides were both detected in human cerebrospinal fluid (CSF) of healthy and AD patients, but no differences in their levels were observed between groups.

    “Aη-α and Aη-β peptides were both detected in human cerebrospinal fluid (CSF) of healthy and AD patients, but no differences in their levels were observed between groups (Willem et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Willem et al., 2015 source

  • It may state two separate claims as one.

    Interpretationcitation

    MT1-MMP upregulation in 5xFAD mice timely and spatially correlates with the increase in C99 levels, providing indirect in vivo support for the pro-amyloidogenic features of this MMP described in HEKswe cells.

    “MT1-MMP upregulation in 5xFAD mice timely and spatially correlates with the increase in C99 levels (Py et al., 2014), thus providing indirect in vivo support for the pro-amyloidogenic features of this MMP described in HEKswe cells (Paumier et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Py et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Paumier et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    Transiently expressed MT1-MMP in HEKswe interacts with APP and induces the release of a soluble APP fragment of ~95 kDa (sAPP95), distinct from sAPPα or sAPPβ generated by α- and β-secretase.

    “Transiently expressed MT1-MMP in HEKswe interacts with APP and induces the release of a soluble APP fragment of ∼95 kDa (sAPP95), distinct of sAPPα or sAPPβ generated by α- and β-secretase, respectively.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Expression of C-terminal truncated APP in human iPS-derived neurons prevented the production of sAPPβ and Aβ, while stimulating α-secretase cleavage.

    “The expression of this C-terminal truncated APP in human iPS-derived neurons prevented the production sAPPβ and Aβ, while stimulating α-secretase cleavage.”
    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.

    Interpretationcitation

    Lowering cholesterol could increase RHBDL4 activity on full-length APP, with consequent generation of CTFs and decrease in Aβ generation.

    “Thus, it is possible that lowering cholesterol could increase RHBDL4 activity on full-length APP, with the consequent generation of CTFs and the decrease in Aβ generation (Paschkowsky et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Paschkowsky et al., 2018 source

  • It may state two separate claims as one.

    Premisecitation

    Mass spectrometry analysis for MT3-MMP cleavage sites revealed the same VLAN579-M580ISEPR site previously identified for MT1-MMP and three other cleavage sites at Ala463-Met464, His622-Ser623 and His685-Gln686.

    “Mass spectrometry analysis for MT3-MMP cleavage-sites revealed the same VLAN579-M580ISEPR site previously identified for MT1-MMP and 3 other cleavage sites at Ala463-Met464, His622-Ser623 and His685-Gln686 (Higashi and Miyazaki, 2003b), the latter being located in the Aβ sequence, just upstream of the α-cleavage site (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Higashi and Miyazaki, 2003b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Replacing the transmembrane domain (TMD) of BACE-1 by that of MT5-MMP did not prevent BACE-1 complex with γ-secretase and Aβ production, suggesting that motifs other than TMD are involved in the formation of the BACE-1/γ-secretase interactions.

    “Replacing the transmembrane domain (TMD) of BACE-1 by that of MT5-MMP did not prevent BACE-1 complex with γ-secretase and Aβ production, suggesting that motifs other than TMD are involved in the formation of the BACE-1/γ-secretase interactions (Liu et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    A ~25 kDa η-CTF was identified in CSF, with higher peptide content in AD patients with a PSEN1 familial mutation, in patients with sporadic AD and in Down Syndrome individuals with Alzheimer's type dementia, compared to age-matched non-demented controls, raising the possibility that η-CTF could be a new disease biomarker.

    “Another study identified a ∼25 kDa η-CTF in CSF, but in this case the peptide content was higher in AD patients with a PSEN1 familial mutation, in patients with sporadic AD and in Down Syndrome individuals with Alzheimer’s type dementia, compared to age-matched non-demented controls, raising the possibility that η-CTF could be a new disease biomarker (Garcia-Ayllon et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Garcia-Ayllon et al., 2017 source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationreasoning

    MT1-MMP cleavage upstream of the β-cleavage site could facilitate β-secretase cleavage of APP and thus the subsequent production of C99 and Aβ.

    “The mechanism by which MT1-MMP could promote amyloidogenesis is still elusive. Nevertheless, reminiscent of legumain, MT1-MMP cleavage upstream of the β-cleavage site could facilitate β-secretase cleavage of APP and thus the subsequent production of C99 and Aβ.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Willem's study did not identify MT1-MMP as cleaving at the VLAN504-M505ISEPR/η-site and concluded that only MT5-MMP could act as a η-secretase in vivo.

    “Intriguingly, the Willem’s study did not identify MT1-MMP as cleaving at this VLAN504-M505ISEPR/η-site and it was concluded that only MT5-MMP could act as a η-secretase in vivo (Willem et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Willem et al., 2015 source

  • It may state two separate claims as one.

    Premisecitation

    MT5-MMP induced the production of a soluble APP fragment of sAPP95 in HEKswe, concomitant with elevated levels of C99 and Aβ40.

    “By the same time, our group demonstrated that MT5-MMP induced the production of a soluble APP fragment of sAPP95 in HEKswe, concomitant with elevated levels of C99 and Aβ40 (Baranger et al., 2016b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baranger et al., 2016b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    About 50% of the sAPP95 released after MT1-MMP expression in HEKswe cells results from concerted action with MMP-2, MT1-MMP being the limiting factor in this enzymatic tandem.

    “It is estimated that about 50% of the sAPP95 released after MT1-MMP expression in HEKswe cells results from concerted action with MMP-2, MT1-MMP being in any case the limiting factor in this enzymatic tandem (Paumier et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Paumier et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    C-terminal truncated forms of Tau show increased polymerization capacity in vitro and are associated with NFTs formation in the brain of AD patients.

    “This is consistent with the observation that C-terminal truncated forms of Tau show increased polymerization capacity in vitro and are associated with NFTs formation in the brain of AD patients (Gamblin et al., 2003; Rissman et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gamblin et al., 2003 source
    • cites Rissman et al., 2004 source

  • It may state two separate claims as one.

    Interpretationcitation

    MT1-MMP could function as a surrogate β-secretase when BACE-1 is inhibited; this is supported by experiments in HEKswe cells where MT1-MMP restores basal levels of Aβ almost abolished by BACE-1 inhibitor IV (or C3).

    “Most interestingly, it has been proposed that MT1-MMP could also function as a surrogate β-secretase when BACE-1 is inhibited; this is supported by experiments in HEKswe cells where MT1-MMP is able to restore the basal levels of Aβ, almost abolished in the presence of BACE-1 inhibitor IV (or C3) (Paumier et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paumier et al., 2019 source
    • The authors state this as an assumption: Reducing Aβ levels below a physiological threshold could have adverse consequences.

  • It may state two separate claims as one.

    Premisecitation

    RHBDL4, but not RHBDL1, RHBDL2 or RHBDL3, cleaves APP at multiple sites within its ectodomain, generating a ~70 kDa N-terminal fragment and different C-terminal fragments.

    “Recently, Paschkowsky et al. (2016) showed in HEK cells expressing APP695 that RHBDL4 but not RHDBL1, 2 and 3, cleaves at multiple sites within the ectodomain of APP (Figure 1) and APLP1 and APLP2, generating a N-terminal fragment of ∼70 kDa and different C-terminal fragments whose functions are still unknown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paschkowsky et al., 2016 source

  • It may state two separate claims as one.

    Premisecitation

    AD brains show elevated levels of caspases, and APP fragments resulting from caspase cleavage colocalize with amyloid plaques.

    “It is also noteworthy that AD brains show elevated levels of caspases and that APP fragments resulting from caspase cleavage colocalize with amyloid plaques (Gervais et al., 1999; Lu et al., 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gervais et al., 1999 source
    • cites Lu et al., 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    η-secretase cleavage of APP generates sAPPη and a residual transmembrane C-terminal APP fragment-η (η-CTF), which accumulates in dystrophic neurites around amyloid plaques in APP/PS1 mice.

    “η-secretase cleavage of APP generates sAPPη and a residual transmembrane C-terminal APP fragment-η (η-CTF), which accumulates in dystrophic neurites around amyloid plaques in APP/PS1 mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Bigenic 5xFAD/legumain−/− and 5xFAD/MT5−/− mice both show significant reductions in Aβ burden and glial reactivity, as well as prevention of LTP and learning and memory deficits.

    “bigenic 5xFAD/legumain–/– and 5xFAD/MT5–/– mice both show significant reductions in Aβ burden and glial reactivity, as well as prevention of LTP and learning and memory deficits (Zhang et al., 2015; Baranger et al., 2016b, 2017a)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Zhang et al., 2015 source
    • cites Baranger et al., 2016b, 2017a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The complementary transmembrane fragment of ~30 kDa (CTF-30) and C99 are dramatically increased and their levels highly correlated, suggesting that CTF-30 may be the precursor of C99.

    “The complementary transmembrane fragment of ∼30 kDa (CTF-30) and C99 are also dramatically increased and their levels highly correlated, suggesting that CTF-30 may be the precursor of C99 (Paumier et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paumier et al., 2019 source

  • It may state two separate claims as one.

    Premisecitation

    High cholesterol levels inhibit RHBDL4 activity, which has been correlated with an increase in the formation of Aβ.

    “high cholesterol levels inhibit RHBDL4 activity, which has been correlated with an increase in the formation of Aβ (Paschkowsky et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Paschkowsky et al., 2018 source

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

    Premisecitation

    Pre-clinical work has reported TIMP-2 as a possible anti-aging factor as it promotes neuronal plasticity and hippocampal-dependent cognition in aging mice.

    “Pre-clinical work has reported TIMP-2 as a possible anti-aging factor as it promotes neuronal plasticity and hippocampal-dependent cognition in aging mice (Castellano et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellano et al., 2017 source

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

    Premisecitation

    TIMPs are known to control cell cycle, cell migration or cell fate also independent of anti-proteinase activities.

    “proteinase inhibitors (e.g., TIMPs), which are known to control cell cycle, cell migration or cell fate also independent of anti-proteinase activities (Baranger et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baranger et al., 2014 source

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

    Premisecitation

    In CSF, one study showed increased TIMP-2 levels in AD patients.

    “in the CSF, two independent studies showed no difference (Mroczko et al., 2014) or increased (Lorenzl et al., 2003a) TIMP-2 levels in AD patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lorenzl et al., 2003a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    In CSF, one study showed no difference in TIMP-2 levels in AD patients.

    “in the CSF, two independent studies showed no difference (Mroczko et al., 2014) or increased (Lorenzl et al., 2003a) TIMP-2 levels in AD patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mroczko et al., 2014 source

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

    Premisecitation

    Patients taking statins, a cholesterol-lowering drug, are still less likely to develop AD.

    “patients taking statins, a cholesterol-lowering drug, are still less likely to develop the disease (Eckert et al., 2005; Fonseca et al., 2010; Wood et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Eckert et al., 2005 source
    • cites Fonseca et al., 2010 source
    • cites Wood et al., 2014 source

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

    Interpretationnone given

    A clear link between high cholesterol levels and the pathogenesis of AD has not yet been confirmed.

    “A clear link between high cholesterol levels and the pathogenesis of AD has not yet been confirmed”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    MT5-MMP can be internalized in endosomes and thus promote endosomal APP sorting.

    “MT5-MMP can be internalized in endosomes (Wang et al., 2004; Baranger et al., 2017a) and thus promote endosomal APP sorting (Baranger et al., 2017a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wang et al., 2004 source
    • cites Baranger et al., 2017a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationnone given

    The available literature on proteinase inhibitors and AD remains essentially correlative and the link between both is to date inconclusive or, at best, speculative.

    “In general, the available literature on proteinase inhibitors and AD remains essentially correlative and the link between both is to date inconclusive or, at best, speculative.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Control of proteolytic activities is an important component of the final proteolytic balance.
80 of 80

  • The paper relies on this without support.

    Targeting the APP proteolytic pathway effectively reduces or prevents pathology and cognitive decline in preclinical experimental models of Alzheimer's disease.

    “Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease”

  • The paper relies on this without support.

    Therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials.

    “but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials.”

  • The paper relies on this without support.

    Aβ is the main driving force behind AD pathology.

    “Aβ, which remains the main driving force behind AD pathology”

  • The paper relies on this without support.

    Findings from mouse models and cultured cells about meprin-β and legumain APP processing can be extrapolated to human AD pathogenesis.

    “In support of these in vitro data, legumain deficiency in the 5xFAD transgenic mouse model of AD (Oakley et al., 2006) causes a drop of Aβ40, Aβ42 and amyloid plaque burden”

  • The paper relies on this without support.

    Aβ oligomers are highly toxic.

    “truncated Aβ species may promote the formation of highly toxic Aβ oligomers.”

  • The paper relies on this without support.

    Tau hyperphosphorylation is a major hallmark of AD pathogenesis.

    “which is a major hallmark of AD pathogenesis.”

  • The authors state this as an assumption.

    Reducing Aβ levels below a physiological threshold could have adverse consequences.

    “if it is assumed that reducing Aβ levels below a physiological threshold could have adverse consequences.”

  • The authors state this as an assumption.

    Control of proteolytic activities is an important component of the final proteolytic balance.

    “assuming that the control of proteolytic activities is an important component of the final proteolytic balance”

  • The paper relies on this without support.

    Aging is by far the main risk factor for AD and other degenerative disorders of nervous and non-nervous tissues.

    “aging is by far the main risk factor for AD and other degenerative disorders of nervous and non-nervous tissues.”

  • The paper relies on this without support.

    The way APP and its metabolites circulate in the cell or between cells affects their functions and their availability for proteolytic processing.

    “Mounting evidence indicates that the way these molecules circulate in the cell (or between cells) affects their functions and their availability for proteolytic processing.”
10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • MT2-MMP is assigned two different membrane anchors

    Minor

    MT2-MMP is listed as both GPI-anchored and anchored by a transmembrane domain. The two classifications conflict within the same description of the six MT-MMPs.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1038/nature07767

    Info

    The cited work was retracted on 2023-12-18 (notice 10.1038/s41586-023-06943-3), not before this paper was published (2019-09-24).

    Cited work 10.1038/nature07767 · retracted 2023-12-18 · notice 10.1038/s41586-023-06943-3 · this paper published 2019-09-24

1 of 1

Citations

Cites

1 retracted

Flagged first, then by citations

2 of the 225 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Metadata

Authors
García-González, L., Pilat, D., Baranger, K., & Rivera, S.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Baranger, Kévin
  • Rivera, Santiago
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2019-09-24
Volume
11
Pages
244-244
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2019.00244
PMC
PMC6769103
OpenAlex
W2969928181
Semantic Scholar
7fd6419a47cbacdb52d3361d9416343d0a53148e
Cited by
88
References
225
Citations by year
2026: 8 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 15 · 2021: 20 · 2020: 8 · 2019: 3
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Aix-Marseille Université
  • Agence Nationale de la Recherche (ANR-15-CE16-0006, ANR-16-COEN-0005)
  • Centre National de la Recherche Scientifique
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid precursor protein, APP processing, MT1-MMP, membrane-type matrix metalloproteinases, beta-secretase, gamma-secretase, meprin beta, legumain, caspases, amyloidogenesis, neuroinflammation, synaptic dysfunction, therapeutic target

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