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

In the paper

“antibodies specifically raised against the Tau1–368 neoepitope were found in AD brains”

What the sources say

• Disputed

  The Online Methods section says the anti-tau N368 antibodies were generated by immunizing mice. In the Results, those antibodies were used to detect tau N368 fragments in human AD brains; the paper does not report finding the antibodies themselves in AD brains. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Zhang et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Wang X. et al., 2017
• Supported

  The Background states that APP is cleaved sequentially by BACE-1 and γ-secretase, producing Aβ peptides. This supports the attributed claim that Aβ results from proteolysis of APP. (LLM, conf=0.94)

  cites Van Acker et al., 2019 source

In the paper

“which in turn promotes astrocyte proliferation (Ogier et al., 2005; Hernandez-Guillamon et al., 2009)”

What the sources say

• Supported

  The Discussion explicitly states that TIMP-1 induces astrocyte proliferation. The Results likewise report that recombinant TIMP-1 produced the largest increase in proliferation in cultured wild-type astrocytes. (LLM, conf=0.94)

  cites Ogier et al., 2005 source
• ?Not checked — no full text of the sourcecites Hernandez-Guillamon et al., 2009 source

In the paper

“which results in modulation of hippocampal synaptic plasticity and neurotransmission in vivo by decreasing the release of synaptic vesicles (Rice et al., 2019)”

What the sources say

• Partly supported

  The section on Schaffer collateral synapses reports that sAPPα alters short-term plasticity and suppresses transmission by reducing release probability through GABABR1a, but those experiments used acute hippocampal slices, not an in vivo preparation. The in vivo section reports reduced CA1 neuronal activity after application of an APP-derived peptide; it does not demonstrate in vivo synaptic plasticity or decreased vesicle release by sAPPα. (LLM, conf=0.88)

  cites Rice et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“thereby providing mechanistic ground for promotion of LTP and synaptic plasticity (Mockett et al., 2019)”

What the sources say

• Supported

  The Significance Statement reports that sAPPα facilitates LTP through protein synthesis and trafficking of GluA2-lacking AMPARs and NMDARs, and that it enhances GluA1 synthesis. The Discussion distinguishes the initial trafficking effect from the longer-term contribution of newly synthesized GluA1, consistent with the claim's broad mechanistic framing. (LLM, conf=0.93)

  cites Mockett et al., 2019 source

In the paper

“many studies using genetic or pharmacological approaches to increase C99 levels in animal models consistently demonstrate the pathogenic properties of C99 linked with AD phenotypes”

What the sources say

• ?Not checked — no full text of the sourcecites Neve et al., 1996 source
• Partly supported

  The Discussion reports AD-like neuronal and synaptic degeneration in mice genetically engineered to express APP-C100, supporting the claim’s core point about a pathogenic C-terminal APP fragment in an animal model. This paper studies APP-C100 rather than specifically establishing increased C99 levels, and it does not demonstrate the claim’s pharmacological approach. The reference to “many studies” also goes beyond what this paper itself demonstrates. (LLM, conf=0.85)

  cites Oster-Granite et al., 1996 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that injected CT105 caused behavioral impairment, gliosis, and neurodegeneration in mice; it also describes neurotoxicity in transgenic animals expressing related APP fragments. This supports the general link between APP carboxyl-terminal fragments and AD-like pathology, but the study injected a 105-amino-acid fragment rather than increasing C99 levels, and it does not establish that genetic or pharmacological C99-increasing studies consistently show this effect. (LLM, conf=0.86)

  cites Song et al., 1998 sourceExperimental — accuracy not yet measured

In the paper

“C99 accumulates in the brains of AD patients (Pera et al., 2013; Kim et al., 2016)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Pera et al., 2013 source
• Supported

  The Results section, “βCTF and endosomal APPL1 levels are elevated in AD brains” (page unavailable), reports significantly elevated βCTF—the APP fragment referred to here as C99—in AD cerebral cortex. The Discussion also describes elevated βCTF levels in sporadic AD brain. (LLM, conf=0.91)

  cites Kim et al., 2016 source

In the paper

“recent data suggest that only a limited fraction of highly diffusible small oligomers have adverse effects, for instance on the disruption of synaptic activity (Hong et al., 2018)”

What the sources say

• Partly supported

  The Introduction reports that a small, diffusible fraction of Aβ carried the toxic activity, and the Results report that diffusible Aβ impaired hippocampal long-term potentiation, a measure of synaptic plasticity. But the Discussion says the precise attributes of the toxic species remain unidentified; the paper does not establish that the active oligomers are small in size or that only a minority of the diffusible oligomers are harmful. No page numbers are available in our copy. (LLM, conf=0.84)

  cites Hong et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“a possible cause of clinical failure could be the difficulty of inhibiting these proteinases without causing side effects resulting from non-targeted proteolytic inhibition on their many physiological substrates”

What the sources say

• ?Not checked — no full text of the sourcecites Karran et al., 2011 source
• Partly supported

  The BACE inhibition as a treatment strategy for AD section attributes failed Phase 3 γ-secretase inhibitor studies to dose-limiting side effects likely related to inhibition of Notch processing or other non-APP substrates. The Outlook section identifies side effects from inhibiting BACE1 functions as a concern, but says severe mechanism-based side effects had not yet been observed in BACE inhibitor clinical trials. Thus the source supports the explanation for γ-secretase inhibitor failure and a possible risk for β-secretase inhibitors, not clinical failure of both therapies. (LLM, conf=0.88)

  cites Vassar et al., 2014 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Failed Drug Trials and Implications for Aβ-Directed Therapies” (page not provided), the review says adverse effects limited trials of a γ-secretase inhibitor. It also warns that β-secretase has more than 20 substrates and that chronic inhibition could cause harm, but describes β-secretase inhibitors as still in development rather than reporting clinical failure of those inhibitors. (LLM, conf=0.86)

  cites De Strooper and Chavez Gutierrez, 2015 sourceExperimental — accuracy not yet measured

In the paper

“human astrocytes derived from induced pluripotent stem cells (iPS) deficient for APP exhibited reduced levels of intracellular cholesterol”

What the sources say

• Supported

  The Results section (‘APP-KO astrocytes have altered cholesterol metabolism’) reports that hiPSC-derived APP-knockout astrocytes had decreased cholesterol compared with wild-type astrocytes. The paper also describes this as decreased intracellular cholesterol in its discussion of full-length APP and cholesterol metabolism. (LLM, conf=0.94)

  cites Fong et al., 2018 source

In the paper

“to highlight its role in APP cleavage at Asn586 that generates the δ-CTF first identified in the nineties (Simons et al., 1996; Scharfenberg et al., 2019).”

What the sources say

• Partly supported

  The Results section ‘AEP cleaves APP at N373 and N585 residues’ identifies legumain/AEP cleavage after Asn585, using APP695 numbering. The Results section ‘AEP interacts with APP in the endolysosomal organelles’ identifies the resulting C-terminal fragment as APP586–695. Thus the paper supports generation of that fragment, but not cleavage at Asn586; it also does not call the fragment δ-CTF in these passages. (LLM, conf=0.88)

  cites Zhang et al., 2015 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results describe a 12 kDa APP C-terminal fragment produced by cleavage upstream of the amyloid-β region, and the Discussion reports a fragment starting at an asparagine residue in APP695. This supports the claim that a corresponding fragment was identified in the 1990s. The paper attributes the cleavage to an unidentified secretase, however; it does not identify legumain as the enzyme. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Simons et al., 1996 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The “β-secretases: BACE and alternatives” section describes meprin β cleavage of APP, including sites near Asp597, but does not address legumain cleavage at Asn586 or formation of δ-CTF. Searches for legumain, Asn586, and δ-CTF found no passage addressing that claim. Page numbers were unavailable in our copy. (LLM, conf=0.74)

  cites Scharfenberg et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Tau1–368 generated by legumain inhibits microtubule polymerization in vitro”

What the sources say

• Partly supported

  The Results section (“AEP cleavage of tau generates neurotoxic fragments”; page not available) reports an in vitro assay in which tau 1–368 had a greatly reduced ability to stimulate microtubule polymerization compared with full-length tau. It does not report that tau 1–368 inhibits polymerization outright. The Introduction identifies AEP as legumain. (LLM, conf=0.88)

  cites Zhang et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“and improves learning and memory.”

What the sources say

• Supported

  In Results, under “Knockout of AEP prevents cognitive deficits in tau P301S mice” (page not provided), the paper reports that deleting Lgmn, the AEP gene, reduced learning deficits and improved memory retention in tau P301S mice. It also reports improved performance in contextual and cued fear-conditioning tests. (LLM, conf=0.94)

  cites Zhang et al., 2014 source

In the paper

“the deletion of legumain in the Tau P301S transgenic mouse model of AD prevents synaptic dysfunction”

What the sources say

• Supported

  In the Results section, the authors report that deleting AEP (encoded by Lgmn, or legumain) in tau P301S mice rescued impaired synaptic transmission and substantially prevented impairment in synaptic function (Fig. 5e,f). The claim is a faithful paraphrase of those findings. (LLM, conf=0.93)

  cites Zhang et al., 2014 source

In the paper

“as well as a reduced ability to endocyte apolipoprotein E (APOE) and Aβ”

What the sources say

• Partly supported

  The Abstract reports impaired Aβ internalization in APP-knockout human iPSC-derived astrocytes, and the Results report reduced uptake of fluorescently labeled LDL. Our copy does not report reduced endocytosis of APOE specifically; the LDL finding does not establish that part of the claim. (LLM, conf=0.88)

  cites Fong et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“The brain of AD patients show increased levels of the Tau1–368 fragment compared to healthy individuals”

What the sources say

• Supported

  The Results section reports that the antibody specific to tau 1–368 detected abundant tau N368 fragments in human AD brains but barely detectable fragments in controls. The Human tissue samples section identifies those controls as nondemented individuals. (LLM, conf=0.94)

  cites Zhang et al., 2014 source

In the paper

“In addition to controlling Tau phosphorylation, legumain generates neurotoxic fragments after cleavage of Tau and APP.”

What the sources say

• Partly supported

  The Introduction identifies legumain as AEP, and the Results section ‘AEP cleavage of tau generates neurotoxic fragments’ reports that AEP-cleaved tau fragments are neurotoxic. Our copy does not establish that AEP cleavage of APP generates neurotoxic fragments; its Online Methods mention only putative APP cleavage sites. (LLM, conf=0.88)

  cites Zhang et al., 2014 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that AEP (legumain) cleaves tau into neurotoxic fragments and cleaves APP to release a neurotoxic APP1–373 fragment. The Results section on APP neurotoxicity reports that the secreted APP1–373 fragment caused neuronal cell death. (LLM, conf=0.92)

  cites Zhang et al., 2015 source

In the paper

“characterized by reduced canonical levels of APP due to exacerbated cleavage of APP by β-secretase.”

What the sources say

• Partly supported

  The Results report reduced full-length APP only in homozygous APPSwe/Swe astrocytes and increased products of β-secretase cleavage, consistent with enhanced cleavage. The claim omits that limitation and characterizes the Swedish mutation generally as reducing APP levels; the paper does not report that reduction in heterozygous APPSwe/WT astrocytes. (LLM, conf=0.85)

  cites Fong et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“meprin-β deletion in mice correlates with higher levels of sAPPα”

What the sources say

• Supported

  The Results section (‘A knock-out of meprin β leads to increased sAPPα secretion in cortical neurons’) reports increased endogenous sAPPα in brain lysates from meprin β knockout mice compared with wild-type mice (Fig. 2a–b). This directly supports the claimed association; the claim does not assert a mechanism. (LLM, conf=0.95)

  cites Schonherr et al., 2016 source

In the paper

“prevented microglial activation”

What the sources say

• Partly supported

  The Results section (“Compound 11 ameliorates Aβ deposition in 5XFAD mice”; page not provided) reports that the legumain inhibitor compound 11 decreased microglial density and inflammatory cytokines in two mouse models. It does not establish that microglial activation was prevented altogether; the measured effects support a reduction, not complete prevention. (LLM, conf=0.84)

  cites Zhang et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The citation is attached to the identification of the 5XFAD transgenic mouse model, not to the claim about legumain deficiency. The Introduction states that Oakley et al. made these mice and describes their Alzheimer’s-like amyloid pathology. (LLM, conf=0.93)

  cites Oakley et al., 2006 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Zhang et al., 2015 source

In the paper

“a chemical inhibitor, which reduced the formation of neurotoxic Tau fragments and Aβ accumulation in P301S and 5xFAD mouse models, respectively.”

What the sources say

• Supported

  The Results section, “Compound 11 ameliorates Aβ deposition in 5XFAD mice,” reports that oral compound 11 inhibited δ-secretase (legumain) activity and reduced amyloid plaque deposition in 5XFAD mice. It also reports significantly lower brain Aβ1–40 and Aβ1–42 concentrations after treatment. (LLM, conf=0.94)

  cites Zhang et al., 2017 source

In the paper

“Willem and collaborators identified by mass spectrometry the VLAN504-M505ISEPR (APP695 numbering) as a cleavage site for MT5-MMP on APP, which was named η-cleavage site (Willem et al., 2015).”

What the sources say

• Supported

  The indexed passage describing Fig. 1f reports mass-spectrometric identification of the APP695 N504/M505 η-cleavage site, with the resulting peptide beginning MISEPRISY. The paper names this processing η-cleavage and reports that MT5-MMP has η-secretase activity, while noting that other enzymes may contribute. (LLM, conf=0.88)

  cites Willem et al., 2015 source

In the paper

“Mint3 can also function as an adaptor protein to promote APP export from the Golgi complex (Caster and Kahn, 2013).”

What the sources say

• Supported

  The Discussion concludes that Mint3 recruitment is critical for APP export from the Golgi in HeLaM cells. The paper also describes Mint3 as an adaptor and reports that disrupting its recruitment delays APP export, supporting the cited paraphrase. (LLM, conf=0.94)

  cites Caster and Kahn, 2013 source

In the paper

“the plasma of young TIMP-2 knockout mice failed to rescue the aged phenotype.”

What the sources say

• Partly supported

  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)

  cites Castellano et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“More recently, it has been shown that BACE-1 can also cleave Aβ40 or Aβ42 to generate a C-terminal truncated Aβ34 form”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Liebsch et al., 2019 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Huse et al., 2002 source

In the paper

“BACE-1 can also catalyze amyloidolytic processing by cleavage between Tyr10 and Glu11 of the Aβ sequence (Huse et al., 2002; Liu et al., 2002; Kimura et al., 2016), the so-called β’-cleavage site (Figure 1).”

What the sources say

• ?Not checked — no full text of the sourcecites Huse et al., 2002 source
• ?Not checked — no full text of the sourcecites Liu et al., 2002 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Kimura et al., 2016 source

In the paper

“Despite controversies over the causes of AD, it is still recognized that brain accumulation of the amyloid peptide-β (Aβ) plays a central role in the pathogenic process (Selkoe and Hardy, 2016).”

What the sources say

• Not checked yetcites Selkoe and Hardy, 2016 source

In the paper

“sAPPβ, which fails to interact with BACE-1 because the truncation of 16 aminoacids at the carboxy end (sequence between the α- and β-cleavage sites) is sufficient to impose significant structural changes compared to sAPPα”

What the sources say

• ?Not checked — no full text of the sourcecites Peters-Libeu et al., 2015 source

In the paper

“Missing relevant Aβ structures as possible therapeutic targets might be one of the reasons why anti-Aβ strategies developed to fight AD have not yet demonstrated significant clinical benefits (Panza et al., 2019)”

What the sources say

• ?Not checked — no full text of the sourcecites Panza et al., 2019 source

In the paper

“the involvement of DR6 in Alzheimer’s neurodegeneration could not be proved in two transgenic mouse models of AD deficient for DR6 (Kallop et al., 2014)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Kallop et al., 2014 source

In the paper

“as well as de novo protein synthesis of GluA1 protein”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Mockett et al., 2019 source

In the paper

“and shows a better correlation than Aβ with the degree of vulnerability to neurodegeneration (Pulina et al., 2019)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Pulina et al., 2019 source

In the paper

“Likewise, sAPPα could rescue LTP in acute hippocampal slices from mice lacking both APP and its family homolog APP-like protein 2 (APLP2) (Hick et al., 2015)”

What the sources say

• ?Not checked — no full text of the sourcecites Hick et al., 2015 source

In the paper

“In cultured neurons from rodents and humans, sAPPα has shown anti-excitotoxic properties through a mechanism involving the reduction of Ca2+ cytotoxic influx (Mattson et al., 1993).”

What the sources say

• ?Not checked — no full text of the sourcecites Mattson et al., 1993 source

In the paper

“likely matching the progression of neuroinflammation and gliosis (Py et al., 2014)”

What the sources say

• ?Not matched

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

  cites Py et al., 2014

In the paper

“C83) can also inhibit Aβ generation by interfering with C99 processing by γ-secretase in HEK cells (Tian et al., 2010)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Tian et al., 2010 source

In the paper

“they also modulate ADAMs activity with low Ki values of 0.5 and 0.1 nM for TIMP-1 and TIMP-3, respectively (Rapti et al., 2008; Baranger et al., 2014)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Rapti et al., 2008 source
• ?Not checked — no full text of the sourcecites Baranger et al., 2014 source

In the paper

“Aβ has been shown to be a positive modulator of synaptic vesicle release (Abramov et al., 2009)”

What the sources say

• ?Not checked — no full text of the sourcecites Abramov et al., 2009 source

In the paper

“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.”

In the paper

“and prevented memory deficits after lentiviral overexpression in the APPswe/PS1dE9 AD mouse model (Tan et al., 2018).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Tan et al., 2018 source

In the paper

“sAPPα stimulates trafficking of GluA2-lacking AMPA and NMDA receptors to the synapse”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Mockett et al., 2019 source

In the paper

“In the diseased brain, reactive astrocytes are the main cellular source of TIMP-1 (Rivera et al., 1997, 2002; Pagenstecher et al., 1998)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Rivera et al., 1997 source
• ?Not checked — no full text of the sourcecites Rivera et al., 2002 source
• ?Not checked — no full text of the sourcecites Pagenstecher et al., 1998

In the paper

“The idea that APP metabolites other than Aβ could actually impact on AD pathology is gaining momentum.”

In the paper

“which could be considered as a neuroprotective cellular response to the amyloid challenge (Rose et al., 2018)”

What the sources say

• ?Not checked — no full text of the sourcecites Rose et al., 2018 source

In the paper

“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.”

In the paper

“highlighting the importance for meprin-β of aminoacid composition around the β-cleavage site (Schonherr et al., 2016).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Schonherr et al., 2016 source

In the paper

“but not in meprin-β knockout mice”

What the sources say

• ?Not checked — no full text of the sourcecites Jefferson et al., 2011 source

In the paper

“Disruptions of physiological functions of APP could cause synaptic dysfunctions that occur in the early phases of AD”

In the paper

“Overall, meprin-β bears great interest as alternative APP processing enzyme with amyloidogenic features.”

In the paper

“that inhibit protein phosphatase 2A (PP2A)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source

In the paper

“APP has also been described as a functional cellular receptor for Aβ”

What the sources say

• ?Not matched

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

  cites Wang Z. et al., 2017

In the paper

“These APP fragments did not induce toxicity in neuronal cultures”

What the sources say

• ?Not checked — no full text of the sourcecites Jefferson et al., 2011 source

In the paper

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

In the paper

“Legumain has been described in relation with AD as a modulator of Tau phosphorylation (Basurto-Islas et al., 2013)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source

In the paper

“the alteration of these functions may indeed contribute to the disease process.”

In the paper

“suggesting that meprin-β can behave as a β-secretase.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“and synaptic transmission (Puzzo et al., 2008, 2011)”

What the sources say

• Not checked yetcites Puzzo et al., 2008 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Puzzo et al., 2011 source

In the paper

“Unlike BACE-1, meprin-β cleaves APP on the plasma membrane before it undergoes endocytosis”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“validating the role of meprin-β in the physiological processing of APP (Jefferson et al., 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Jefferson et al., 2011 source

In the paper

“The complexity of interactions between APP and canonical secretases results in multifunctional derivatives of APP (Chen et al., 2015; Liu et al., 2019).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Chen et al., 2015 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Liu et al., 2019 source

In the paper

“N-APP were detected in mice brains as well as in the brains of healthy individuals and patients with AD”

What the sources say

• ?Not checked — no full text of the sourcecites Jefferson et al., 2011 source

In the paper

“These few examples illustrate the importance of canonical APP as a regulator of tissue homeostasis”

In the paper

“mice virally infected with uncleavable Tau mutant showed reduced pathological and behavioral defects as compared with mice infected with Tau P301S.”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“Aβ oligomers isolated from AD brains require APP expression to induce synaptotoxic effects on mice hippocampi (Wang Z. et al., 2017)”

What the sources say

• ?Not matched

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

  cites Wang Z. et al., 2017

In the paper

“Another work highlights the potential of full length APP as functional receptor for the regulation of cholesterol/lipoprotein metabolism and Aβ clearance (Fong et al., 2018).”

What the sources say

• Not checked yetcites Fong et al., 2018 source

In the paper

“several studies have reported increased mRNA and protein levels of meprin-β in AD patients compared to age-matched healthy individuals (Bien et al., 2012; Schlenzig et al., 2018).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Schlenzig et al., 2018 source

In the paper

“where it cleaves I2PP2A (also known as SET).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source

In the paper

“and the extent to which subtle alterations in its biology could trigger or accompany pathological processes.”

In the paper

“as opposed to the lack of effect of distal mutations (i.e., London (V717I)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Schonherr et al., 2016 source

In the paper

“suggesting in vivo competition with α-secretase for membrane-bound APP (Schonherr et al., 2016).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Schonherr et al., 2016 source

In the paper

“a key phosphatase that limits Tau hyperphosphorylation both in vitro (Basurto-Islas et al., 2013) and in vivo (Basurto-Islas et al., 2018).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source
• ?Not checked — no full text of the sourcecites Basurto-Islas et al., 2018 source

In the paper

“which is more prone to aggregation than Aβ1–40.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“and absent in legumain knockout mice”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“and promotes apoptosis in rat cultured neurons.”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“In the nervous system, meprin-β has been described as a new alternative APP processing enzyme, which links its activity to AD (reviewed in Scharfenberg et al., 2019).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Scharfenberg et al., 2019 source

In the paper

“Aβ2–X can only be generated by membrane-bound meprin-β and not by the soluble form after ADAM10/17-mediated shedding (Bien et al., 2012).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“meprin-β expression in BACE-1/2 knockout fibroblasts was sufficient to generate Aβ (Bien et al., 2012).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“the inhibition of β-secretase reversed these effects”

What the sources say

• Not checked yetcites Fong et al., 2018 source

In the paper

“Under acidic conditions (e.g., brain ischemia, hypoxia, or AD), legumain can translocate from neuronal lysosomes into the cytoplasm”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source
• ?Not checked — no full text of the sourcecites Basurto-Islas et al., 2018 source

In the paper

“thus validating in vivo legumain-mediated Tau processing (Zhang et al., 2014).”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“APP mutations proximal to the β-cleavage site, like the Swedish (K670N-M671L) or the “protective” Icelandic (A673T), prevent the generation of Aβ2–X by meprin-β”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Schonherr et al., 2016 source

In the paper

“highlighting the potential benefits of such inhibition specifically in astrocytes (Fong et al., 2018).”

What the sources say

• Not checked yetcites Fong et al., 2018 source

In the paper

“This cleavage generates two fragments, I2NTF and I2CTF”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Basurto-Islas et al., 2013 source

In the paper

“Similar deficits have been observed in astrocytes expressing APP harboring the Swedish familial mutation”

What the sources say

• Not checked yetcites Fong et al., 2018 source

In the paper

“meprin-β can cleave APP near the N-terminal end to generate truncated fragments of 11 and 20 kDa (N-APP)”

What the sources say

• ?Not checked — no full text of the sourcecites Jefferson et al., 2011 source

In the paper

“In total, legumain activity promotes the hyperphosphorylation of Tau protein”

In the paper

“in correlation with increased levels of legumain activity (Zhang et al., 2014).”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“Similarly to MT1-MMP, we found that MT5-MMP could interact with APP and promote its endosomal sorting, thereby providing mechanistic support for MT5-MMP pro-amyloidogenic activity (Baranger et al., 2017a).”

What the sources say

• ?Not matched

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

  cites Baranger et al., 2017a

In the paper

“Several studies have demonstrated in a variety of culture cell systems the ability of caspase-3, -6 and -8 to cleave APP, mainly between amino acids V664-D665 (APP695 numbering) within the intracytoplasmic domain (Gervais et al., 1999; LeBlanc et al., 1999; Pellegrini et al., 1999; Weidemann et al., 1999).”

What the sources say

• ?Not checked — no full text of the sourcecites Gervais et al., 1999 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites LeBlanc et al., 1999 source
• ?Not checked — no full text of the sourcecites Pellegrini et al., 1999 source

In the paper

“Although the exact nature of sAPP95 produced upon MT1-MMP and MT5-MMP expression needs to be established, it likely corresponds to what was defined as sAPPη by others (Willem et al., 2015).”

What the sources say

• Not checked yetcites Willem et al., 2015 source

In the paper

“Moreover, the fact that Aη-α levels are exacerbated upon BACE-1 inhibition may raise concerns of possible side effects of therapeutic anti-BACE-1 strategies.”

In the paper

“a chemical inhibitor, which reduced the formation of neurotoxic Tau fragments and Aβ accumulation in P301S and 5xFAD mouse models, respectively.”

What the sources say

• Not checked yetcites Zhang et al., 2017 source

In the paper

“while it increases spine density”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Zhang et al., 2015 source

In the paper

“Most important, 5xFAD/MT5–/– mice showed strikingly lower levels of Aβ (soluble Aβ40 and Aβ42, oligomers and plaques) and C99 at prodromal-like stages of the pathology (Baranger et al., 2016b, 2017a).”

What the sources say

• ?Not matched

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

  cites Baranger et al., 2016b
• ?Not matched

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

  cites Baranger et al., 2017a

In the paper

“It is also noteworthy that MT1-MMP content is strongly upregulated in the cortex and hippocampus of 6-month old 5xFAD mice (Py et al., 2014).”

What the sources say

• ?Not matched

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

  cites Py et al., 2014

In the paper

“Recombinant Aη-α was able to impair LTP when incubated on primary rat neuronal cultures.”

In the paper

“From a functional standpoint, the absence of MT5-MMP prevented deficits in LTP and spatial and working memory observed in 5xFAD mice (Baranger et al., 2016b, 2017a).”

What the sources say

• ?Not matched

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

  cites Baranger et al., 2016b
• ?Not matched

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

  cites Baranger et al., 2017a

In the paper

“Using specific antibodies against the neoepitopes of the α-, β- and η-sites, it was observed that BACE-1 inhibition promoted the release of a peptide Aη-α (for amyloid eta-alpha) resulting from the combined action of MT5-MMP and α-secretase.”

In the paper

“In addition, the inhibition of ADAM10 promoted the concerted action of MT5-MMP and BACE-1 to release a shorter peptide, Aη-β, unexpectedly innocuous (Willem et al., 2015).”

What the sources say

• Not checked yetcites Willem et al., 2015 source

In the paper

“Indeed, a recent study has shown that MT5-MMP does not co-purify in the high molecular weight complex formed by BACE-1 and γ-secretase.”

In the paper

“In complement of these results, we have recently reported that MT1-MMP can also prominently increase Aβ levels in the HEK293 cell model of amyloidogenesis, which stably expresses APP with the familial Swedish mutation (HEKswe) (Paumier et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Paumier et al., 2019 source

In the paper

“Although the APP cleavage sites for MT1-MMP and MT5-MMP were not specifically identified in the Ahmad study, the analysis of the APP degradation profile by western blot suggested that both MT-MMPs should cleave APP at the same location as MT3-MMP (Ahmad et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Ahmad et al., 2006 source

In the paper

“and prevents deficits in LTP and learning and memory (Zhang et al., 2015).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Zhang et al., 2015 source

In the paper

“A plausible scenario would be that activation of MMP-2 by MT1-MMP (Sato et al., 1996) allows MMP-2 access to membrane substrates (i.e., APP), which would not otherwise be accessible for this soluble MMP.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Sato et al., 1996 source