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Cited by 39Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtease and Inhibitor Mechanisms

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

Open access
Nakamura, Mai, Li, Yuhan, Choi, Bo-Ran, Matas-Rico, Elisa, Troncoso, Juan, Takahashi, Chiaki, Sockanathan, Shanthini·2021·Science Translational Medicine
DOI 10.1126/scitranslmed.abe6178PMC PMC8085789
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Abstract

GDE2 controls surface amounts of the metalloprotease inhibitor RECK to promote ADAM10 α-secretase activity and prevent Aβ production and synapse loss.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper identifies GDE2 as a regulator of ADAM10 α-secretase via shedding and inactivating GPI-anchored RECK; in AD brain, GDE2 accumulates intracellularly and membrane-tethered RECK rises. In mice, GDE2 loss increases membrane RECK, shifts APP processing toward amyloidogenic sAPPβ/Aβ, reduces synaptic proteins, and RECK reduction rescues these phenotypes.

Key findings

  • In human AD cortex, GDE2 accumulates in neuronal soma (GDE2high neurons were specific to AD and not seen in HD), while membrane-tethered RECK is elevated and released RECK is reduced by approximately 50% in BA40 and BA9, with no change in total RECK or the non-GDE2 substrate CNTN1.
  • Aged 19-month Gde2−/− cortex shows a 16% reduction in sAPPα, a 121% rise in sAPPβ, and a 64% reduction in sAPPα:sAPPβ ratio; cultured Gde2−/− cortical neurons show a 63% reduction in sAPPα and a 96% increase in sAPPβ. Postnatal GDE2 ablation reduces GDE2 by 75%, sAPPα by 50%, increases sAPPβ by 60%, and reduces sAPPα:sAPPβ ratios by 80%.
  • GDE2 loss increases Aβ42 by 20% and Aβ40 by 4% in 19-month cortex; in APP/PS1;Gde2−/− mice, TBS- and formic acid-soluble Aβ40/Aβ42 increase 8–10 fold and plaques appear at 4 months, 2 months earlier than usual. Synaptic proteins and synapse puncta are reduced, with approximately 20% fewer synaptophysin/PSD95 puncta.
  • Reducing RECK rescues the phenotype: Gde2−/−;Reck+/− mice have 62% lower RECK, 58% higher sAPPα, 30% lower sAPPβ, and 72% higher sAPPα:sAPPβ ratios, with increased synaptic proteins; Reck siRNA reduces Aβ42 by 35% in Gde2−/− neurons and by 70% in APP/PS1;Gde2−/− neurons.

Methods

  • Human postmortem tissue: BA40 and BA9 cortex from controls, AD Braak V/VI, AD Braak III/IV, and HD cases; immunohistochemistry with validated GDE2 antibodies, Triton X-114 fractionation, and Western blot.
  • Mouse and cell models: Gde2−/−, APP/PS1, Reck+/−, and ROSACreER;Gde2lox/− mice with tamoxifen at P10/P11; primary cortical neuron cultures, lentiviral CD2RECK, Reck siRNA, BACE inhibitor C3, and heterologous COS-7/HEK293FT/U-2 OS cells.
  • Assays and analysis: Western blot densitometry, surface biotinylation, sandwich ELISA for Aβ40/Aβ42, immunostaining/confocal imaging, calcium imaging; statistics used two-tailed unpaired Student’s t-test, p<0.05, mean ± SEM, with at least 3 biological replicates per condition.

Limitations

  • Stated: the mechanistic studies are performed primarily in mouse models; in-depth functional studies in human neurons are needed, and model organisms have sometimes failed to translate to human disease.
  • Stated/evident: human evidence is postmortem observational (immunohistochemistry and biochemical fractionation) showing association, not causality; no functional rescue in human neurons is reported.
  • Evident: the mechanisms for increased sAPPβ and the skew toward Aβ42 remain unclear, and potential effects of GDE2-RECK on BACE are likely indirect and not fully resolved.

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

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.abe6178

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

32 of 55 cited sources checked · 18 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ADAM10 cleaves APP to generate soluble APPα (sAPPα).

    “ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ”
    • Also stated in: § Introduction: · plain
      “cleaves APP proximal to the β-secretase site and releases sAPPα, a soluble, neuroprotective N-terminal fragment (3, 5).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF, ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29, 3020– 3032 (2010). 20676056 PMC2944055 source
    • cites [5] Lichtenthaler SF, Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Curr Alzheimer Res 9, 165– 177 (2012). 21605033 source
  • Interpretationcitation

    GDE2 functions as an activator of ADAM10 cleavage function by regulating RECK expression on the plasma membrane.

    “Thus, GDE2 functions as an activator of ADAM10 cleavage function by regulating RECK expression on the plasma membrane.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source
  • Premisecitation

    ADAM10 is the major α-secretase that cleaves APP in neurons.

    “genetic ablation and knockdown studies identify ADAM10 as the major α-secretase that cleaves APP in neurons (3, 4).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF, ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29, 3020– 3032 (2010). 20676056 PMC2944055 source
    • cites [4] Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L, Snellinx A, Craessaerts K, Thathiah A, Tesseur I, Bartsch U, Weskamp G, Blobel CP, Glatzel M, De Strooper B, Saftig P, The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci 30, 4833– 4844 (2010). 20371803 PMC2921981 source
  • Premisecitation

    In the developing nervous system, ADAM10 activity is regulated by the GDE2-RECK pathway.

    “In the developing nervous system, ADAM10 activity is regulated by the GDE2-RECK pathway.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source
  • Premisecitation

    sAPPα is neuroprotective.

    “ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ”
    • Also stated in: § Introduction: · plain
      “releases sAPPα, a soluble, neuroprotective N-terminal fragment (3, 5).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF, ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29, 3020– 3032 (2010). 20676056 PMC2944055 source
    • cites [5] Lichtenthaler SF, Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Curr Alzheimer Res 9, 165– 177 (2012). 21605033 source
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Premisecitation

    RECK inactivation leads to ADAM10 shedding of Dll1, downregulation of Notch signaling in adjacent progenitors and induction of neuronal differentiation.

    “RECK inactivation leads to ADAM10 shedding of the Notch ligand Delta-like 1 (Dll1), downregulation of Notch signaling in adjacent progenitors and induction of neuronal differentiation (Figure S1A) (26).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source

  • May combine two claims.

    Premisecitation

    During embryonic neurogenesis, GDE2 promotes ADAM10 activity by cleaving RECK at the GPI-anchor and removing RECK from neuronal surfaces.

    “During embryonic neurogenesis, GDE2 promotes ADAM10 activity by cleaving RECK at the GPI-anchor and removing RECK from neuronal surfaces (26).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    sAPPα interacts with β-secretase to inhibit its cleavage of APP, further stimulating non-amyloidogenic APP processing.

    “sAPPα interacts with β-secretase to inhibit its cleavage of APP, to further stimulate non-amyloidogenic APP processing (6).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Obregon D, Hou H, Deng J, Giunta B, Tian J, Darlington D, Shahaduzzaman M, Zhu Y, Mori T, Mattson MP, Tan J, Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. Nat Commun 3, 777 (2012). 22491325 PMC3520614 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GDE2 is one of three known GPI-anchor cleaving enzymes in vertebrates and the only one expressed in neurons.

    “GDE2 is one of three known GPI-anchor cleaving enzymes in vertebrates that function at the cell surface, and the only one expressed in neurons (22–26).”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [22] Yanaka N, Mammalian glycerophosphodiester phosphodiesterases. Biosci Biotechnol Biochem 71, 1811– 1818 (2007). 17690467 source
    • cites [23] Rao M, Sockanathan S, Transmembrane protein GDE2 induces motor neuron differentiation in vivo. Science 309, 2212– 2215 (2005). 16195461 source
    • cites [24] Sabharwal P, Lee C, Park S, Rao M, Sockanathan S, GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling. Neuron 71, 1058– 1070 (2011). 21943603 PMC3183458 source

      The Results section (“GDE2 expression in spinal motor neurons”; page unavailable) documents GDE2 expression in motor neurons. The Discussion says GDE2’s direct substrates had not been definitively identified; our copy does not establish that it cleaves GPI anchors, that there are three such vertebrate enzymes, or that GDE2 alone is expressed in neurons. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [25] Rodriguez M, Choi J, Park S, Sockanathan S, Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation. Development 139, 3870– 3879 (2012). 22951639 source
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source

      The paper reports GDE2-mediated GPI-anchor cleavage at the cell surface and names two previously identified vertebrate GPI-anchor-cleaving enzymes (Abstract; page unavailable). It does not establish that exactly three such enzymes function at the cell surface or that GDE2 is the only one expressed in neurons; it also describes GDE3 and GDE6 as sharing cleavage activity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mutations of ADAM10 that reduce its activity enhance amyloidogenic APP processing and Aβ deposition and are linked to late-onset AD.

    “Mutations of ADAM10 that reduce its activity and enhance amyloidogenic APP processing and Aβ deposition have recently been linked to late-onset AD (LOAD) (10, 11), establishing ADAM10 as a susceptibility gene for AD.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE, Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet 18, 3987– 3996 (2009). 19608551 PMC2748890 source

      The Discussion reports that Q170H and R181G reduce ADAM10 α-secretase activity, increase Aβ levels in cultured cells, and occur in families with late-onset AD. It does not show that these mutations increase Aβ deposition; it also describes ADAM10 as a possible or candidate susceptibility gene rather than an established one. The APP-processing results did not detect an increase in β-cleavage fragments. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [11] Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE, ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80, 385– 401 (2013). 24055016 PMC4105199 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Surface trafficking pathways mediated in part by tetraspanin proteins contribute to ADAM10 α-cleavage activity.

    “emerging studies indicate contributions of surface trafficking pathways that are mediated in part by tetraspanin proteins (15–17).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Xu D, Sharma C, Hemler ME, Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J 23, 3674– 3681 (2009). 19587294 PMC2775005 source

      The Discussion (Mechanistic insights) links TSPAN12 localization to ADAM10 function: a mutant partly diverted TSPAN12 from the plasma membrane and impaired ADAM10 maturation and activity. The paper supports a tetraspanin contribution to ADAM10 α-cleavage, but does not establish a surface-trafficking pathway for ADAM10; it reports that TSPAN12 manipulation did not change ADAM10 levels at the cell surface. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [16] Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, Herdewijn P, Staes A, Timmerman E, Vandekerckhove J, Rubinstein E, Boucheix C, Gevaert K, De Strooper B, Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol 11, 1340– 1346 (2009). 19838174 source
    • cites [17] Jouannet S, Saint-Pol J, Fernandez L, Nguyen V, Charrin S, Boucheix C, Brou C, Milhiet PE, Rubinstein E, TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization. Cell Mol Life Sci 73, 1895– 1915 (2016). 26686862 PMC4819958 source

  • Classified as probably not a substantial claim.

    Premisecitation

    ADAM10 is a susceptibility gene for AD.

    “establishing ADAM10 as a susceptibility gene for AD.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE, Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet 18, 3987– 3996 (2009). 19608551 PMC2748890 source

      The Abstract calls ADAM10 a “candidate AD susceptibility gene” and reports evidence of an association with AD. The Results section notes that the initially tested SNPs did not show an association in an independent sample. The citing sentence’s “establishing” overstates the paper’s qualified conclusion. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [11] Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE, ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80, 385– 401 (2013). 24055016 PMC4105199 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ADAM10 α-cleavage activity is influenced by growth factors, cytokines and neurotransmitters.

    “Post-translationally, ADAM10 α-cleavage activity is influenced by growth factors, cytokines and neurotransmitters”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Xu D, Sharma C, Hemler ME, Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J 23, 3674– 3681 (2009). 19587294 PMC2775005 source

      The Abstract and Discussion report that TSPAN12 promotes ADAM10 maturation and α-secretase activity, supporting post-translational regulation of that activity. They describe growth factors and TNF-α as molecules ADAM10 cleaves, not as regulators of its α-cleavage activity; the copy does not establish regulation by growth factors, cytokines, or neurotransmitters. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [16] Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, Herdewijn P, Staes A, Timmerman E, Vandekerckhove J, Rubinstein E, Boucheix C, Gevaert K, De Strooper B, Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol 11, 1340– 1346 (2009). 19838174 source
    • cites [17] Jouannet S, Saint-Pol J, Fernandez L, Nguyen V, Charrin S, Boucheix C, Brou C, Milhiet PE, Rubinstein E, TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization. Cell Mol Life Sci 73, 1895– 1915 (2016). 26686862 PMC4819958 source

      The Introduction (page unavailable) says ADAM10 activity can be stimulated by calcium ionophores, P2X7 receptor activation and antibodies against tetraspanins, supporting the general point that its cleavage activity is regulated. It does not identify growth factors, cytokines or neurotransmitters as regulators; it describes growth factors and cytokines as substrates of shedding. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PRDX4 thiol oxidation of GDE2 in the ER-trans Golgi network prevents trafficking of mature GDE2 to the plasma membrane and leads to GDE2 intracellular sequestration.

    “In contrast, PRDX4 thiol oxidation of GDE2 in the ER-trans Golgi network prevents trafficking of mature GDE2 to the plasma membrane and leads to GDE2 intracellular sequestration (46).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] Yan Y, Wladyka C, Fujii J, Sockanathan S, Prdx4 is a compartment-specific H2O2 sensor that regulates neurogenesis by controlling surface expression of GDE2. Nat Commun 6, 7006 (2015). 25943695 PMC4432624 source

      The Results (‘Prdx4 inhibits GDE2 through thiol oxidation’ and ‘Prdx4 inhibits GDE2 surface trafficking’; page unavailable) support GDE2 thiol oxidation and reduced surface expression in the presence of Prdx4. The Discussion places the proposed inhibition of trafficking within the ER, not the ER–trans-Golgi network; the cited passages also do not establish that the sequestered GDE2 is mature. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    GDE2-PRDX1 thiol reduction stimulates GDE2 activity at the cell surface.

    “GDE2-PRDX1 thiol reduction stimulates GDE2 activity at the cell surface (45).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Yan Y, Sabharwal P, Rao M, Sockanathan S, The antioxidant enzyme Prdx1 controls neuronal differentiation by thiol-redox-dependent activation of GDE2. Cell 138, 1209– 1221 (2009). 19766572 PMC2748999 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GDE2 is the only known GPI-anchor cleaving enzyme in vertebrates that functions at the cell surface in neurons to release GPI-anchored proteins into the extracellular space.

    “GDE2 is the only known GPI-anchor cleaving enzyme in vertebrates that functions at the cell surface in neurons to release GPI-anchored proteins into the extracellular space (26)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source

      The paper reports that GDE2 releases GPI-anchored RECK from the cell surface into the medium and links this activity to spinal motor neuron differentiation (Abstract; Fig. 3F). It does not establish that GDE2 is the only vertebrate enzyme with this function in neurons; it also describes GPI-anchor cleavage as an activity shared by GDE3 and GDE6. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Brains of patients with AD exhibit prominent hallmarks of oxidative damage and decreased PRDX1 acetylation and thiol-reductive activity.

    “Brains of patients with AD exhibit prominent hallmarks of oxidative damage and decreased PRDX1 acetylation and thiol-reductive activity (47, 48) that could collectively impair GDE2 trafficking and function.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [47] Butterfield DA, Drake J, Pocernich C, Castegna A, Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7, 548– 554 (2001). 11733217 source
    • cites [48] Choi H, Kim HJ, Kim J, Kim S, Yang J, Lee W, Park Y, Hyeon SJ, Lee DS, Ryu H, Chung J, Mook-Jung I, Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Abeta-induced impaired axonal transport. Mol Neurodegener 12, 23 (2017). 28241840 PMC5330132 source

      The Results section reports decreased PRDX1 acetylation in the hippocampus and entorhinal cortex of patients with AD, and cites elevated oxidative-damage markers in AD brains (page not available). The paper links PRDX1 acetylation to antioxidant function, but does not report a measurement of decreased thiol-reductive activity in patient brains; its activity evidence comes from cell experiments and a cited prior study. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antisense oligonucleotides (ASOs) have proved effective in treating diseases such as spinal muscular atrophy (SMA) in human patients.

    “Antisense oligonucleotides (ASOs) have proved effective in treating diseases such as spinal muscular atrophy (SMA) in human patients (49, 50); accordingly, the development of ASOs targeting RECK could be one possible intervention to mitigate pathologies associated with amyloidogenic APP processing (2, 51).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [49] Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC, Group ES, Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med 377, 1723– 1732 (2017). 29091570 source
    • cites [50] Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K, Shieh PB, Tulinius M, Mazzone ES, Montes J, Bishop KM, Yang Q, Foster R, Gheuens S, Bennett CF, Farwell W, Schneider E, De Vivo DC, Finkel RS, Group CS, Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med 378, 625– 635 (2018). 29443664 source

  • May combine two claims.

    Interpretationreasoning

    GDE2 trafficking and function are disrupted in neurons of patients with AD.

    “Because GDE2 function requires expression on the cell surface (26, 29), these observations suggest that GDE2 trafficking and function are disrupted in neurons of patients with AD.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [26] Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S, GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339, 324– 328 (2013). 23329048 PMC3644959 source
    • cites [29] Salgado-Polo F, van Veen M, van den Broek B, Jalink K, Leyton-Puig D, Perrakis A, Moolenaar WH, Matas-Rico E, Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation. J Cell Sci 133, (2020). PMC7033719 31932507 source
    • Rests on an assumption: The GDE2-RECK-ADAM10 mechanism identified in mouse models and cultured neurons operates in the human AD brain.
    • Rests on an assumption: Postmortem human brain tissue protein levels and distributions reflect the antemortem state relevant to AD.

  • May combine two claims.

    Findingown data

    GDE2 and RECK are not downregulated postnatally but continue to be expressed in adult brain.

    “Unlike most developmental pathways, GDE2 and RECK are not downregulated postnatally but continue to be expressed in adult brain (Figure 1A–D, Figure S2, Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Braak III/IV AD, GDE2high neurons are evident and neurons with more intense hGDE2 somatic immunoreactivity are detected.

    “In patients with Braak III/IV AD where degeneration of neocortex is minimal, GDE2high neurons are evident and neurons with more intense hGDE2 somatic immunoreactivity are detected (Figure 1D, Figure S4, Table S1, Datafile S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hGDE2 does not accumulate in neurons of BA40 cortex from age and gender-matched HD patients and expression appears equivalent to controls.

    “hGDE2 does not accumulate in neurons of BA40 cortex from age and gender-matched patients with HD and hGDE2 expression appears equivalent to controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The cellular and biochemical changes of GDE2 accumulation and increased membrane-associated RECK were not observed in the brain of patients with HD.

    “Interestingly, these cellular and biochemical changes were not observed in the brain of patients with HD, arguing against a general disruption of the GDE2/RECK pathway in degenerating neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ablation of GDE2 in mice results in increased membrane-associated RECK and reduced released RECK, with no change in total RECK expression.

    “ablation of GDE2 in mice (Gde2−/−) results in increased amounts of membrane-associated RECK and reduced amounts of released RECK, with no change in total RECK expression (Figure S5B, Datafile S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ADAM10, BACE and APP expression are equivalent between genotypes in postnatal GDE2 ablation.

    “ADAM10, BACE and APP expression were equivalent between genotypes (Figure 3C, Figure S7C, Datafile S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In human postmortem tissue, GDE2 accumulated abnormally in intracellular compartments in neurons in the brain of patients with AD, and this accumulation paralleled increases in membrane-associated RECK.

    “Our studies of human postmortem tissue revealed that GDE2 accumulated abnormally in intracellular compartments in neurons in the brain of patients with AD, and this accumulation paralleled increases in membrane-associated RECK.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    siRNA knockdown of Reck by approximately 50% in APP/PS1; Gde2−/− neurons resulted in robust reduction of Aβ peptides and improved Aβ40/42 ratios.

    “Importantly, siRNA knockdown of Reck by approximately 50% in APP/PS1; Gde2−/− neurons resulted in robust reduction of Aβ peptides and improved Aβ40/42 ratios.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In tamoxifen-treated RosaCreER;Gde2lox/− mice, sAPPα is reduced by 50%, sAPPβ increased by 60%, and sAPPα:sAPPβ ratios reduced by 80%.

    “sAPPα was reduced by 50% in treated RosaCreER;Gde2lox/− mice, with a 60% increase in sAPPβ, and a corresponding 80% reduction in sAPPα:sAPPβ ratios (Figure 3C, Datafile S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • May combine two claims.

    Findingown data

    In Gde2−/− cortical extracts and cultured cortical neurons, the increase in Aβ40 was modest, whereas the increase in Aβ42 peptides was more robust.

    “Interestingly, the increase in Aβ40 was modest, whereas the increase in Aβ42 peptides was more robust, and this pattern was observed in Gde2−/− cortical extracts and cultured cortical neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Gde2−/− mice lack GDE2 activity and exhibit increased amounts of membrane-tethered surface RECK.

    “Gde2−/− mice phenocopy GDE2-RECK abnormalities in the brain of patients with AD in that they lack GDE2 activity and exhibit increased amounts of membrane-tethered surface RECK (Figure S5B–C, Datafile S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.

  • May combine two claims.

    Findingown data

    In aged 19-month Gde2−/− cortices, sAPPα is reduced by 16% and sAPPβ is increased by 121% compared with WT, resulting in a 64% reduction in sAPPα:sAPPβ ratios.

    “Western blot of protein extracts prepared from aged 19-month cortices show a 16% reduction in sAPPα and a concomitant 121% rise in sAPPβ in Gde2−/− mice compared with wildtype (WT), resulting in a 64% reduction in sAPPα:sAPPβ ratios (Figure 3A, Datafile S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • May combine two claims.

    Findingown data

    Similar increases in membrane-tethered RECK and reductions in released RECK are found in BA9 prefrontal cortex of Braak V/VI AD patients compared with controls.

    “Similar observations were found for BA9 prefrontal cortex comparing patients with Braak V/VI-stage AD and controls (Figure 2B, Datafile S1)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Postmortem human brain tissue protein levels and distributions reflect the antemortem state relevant to AD.

  • May combine two claims.

    Findingown data

    In 19-month Gde2−/− cortical extracts, Aβ42 is increased by 20%, Aβ40 by 4%, and Aβ40/42 ratios are reduced compared with WT.

    “Enzyme-linked immunosorbent assays (ELISA) showed a marked 20% increase in Aβ42, a modest 4% increase in Aβ40 and reduced Aβ40/42 ratios in 19-month Gde2−/− cortical extracts compared to WT (Figure 4A, Datafile S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.

  • May combine two claims.

    Findingown data

    Cultured Gde2−/− cortical neurons at 14 DIV show a 63% reduction in sAPPα, a 96% increase in sAPPβ, and decreased sAPPα:sAPPβ ratios.

    “Western blots of extracts prepared from cultured Gde2−/− cortical neurons showed a dramatic 63% reduction in sAPPα, a 96% increase in sAPPβ, and a resulting decrease in sAPPα:sAPPβ ratios (Figure 3B, Datafile S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ADAM10 transcript expression is regulated by retinoic acid.

    “ADAM10 transcript expression is regulated by retinoic acid (13)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Prinzen C, Muller U, Endres K, Fahrenholz F, Postina R, Genomic structure and functional characterization of the human ADAM10 promoter. FASEB J 19, 1522– 1524 (2005). 15972296 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ADAM10 is tightly regulated through transcription, translation and post-translational mechanisms.

    “Studies in the last decade have indicated that ADAM10 is tightly regulated through transcription, translation and post-translational mechanisms (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lichtenthaler SF, Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Curr Alzheimer Res 9, 165– 177 (2012). 21605033 source

  • May combine two claims.

    Study design and conductown data

    The rαhGDE2 and cSS1 antibodies specifically detect hGDE2 protein.

    “These experiments verify that both rαhGDE2 and cSS1 antibodies specifically detect hGDE2 protein.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    RECK is a GPI-anchored protein that binds and inhibits metalloproteases including ADAM10.

    “RECK is a GPI-anchored protein that binds and inhibits metalloproteases that include ADAM10 (18–21).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [18] Alexius-Lindgren M, Andersson E, Lindstedt I, Engstrom W, The RECK gene and biological malignancy--its significance in angiogenesis and inhibition of matrix metalloproteinases. Anticancer Res 34, 3867– 3873 (2014). 25075007
    • cites [19] Rhee JS, Coussens LM, RECKing MMP function: implications for cancer development. Trends Cell Biol 12, 209– 211 (2002). 12062160 source
    • cites [20] Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, Noda M, The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789– 800 (2001). 11747814 source
    • cites [21] Muraguchi T, Takegami Y, Ohtsuka T, Kitajima S, Chandana EP, Omura A, Miki T, Takahashi R, Matsumoto N, Ludwig A, Noda M, Takahashi C, RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci 10, 838– 845 (2007). 17558399 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ADAM10 translation can be blocked through 5' regulatory sequences.

    “its translation can be blocked through 5’ regulatory sequences, although the mechanisms underlying this control are not well understood (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Lammich S, Buell D, Zilow S, Ludwig AK, Nuscher B, Lichtenthaler SF, Prinzen C, Fahrenholz F, Haass C, Expression of the anti-amyloidogenic secretase ADAM10 is suppressed by its 5’-untranslated region. J Biol Chem 285, 15753– 15760 (2010). 20348102 PMC2871442 source

  • May combine two claims.

    Premisecitation

    RECK directly binds ADAM10 and inhibits ADAM10 activity in a dose-dependent manner.

    “RECK directly binds ADAM10, inhibits ADAM10 activity in a dose-dependent manner”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Muraguchi T, Takegami Y, Ohtsuka T, Kitajima S, Chandana EP, Omura A, Miki T, Takahashi R, Matsumoto N, Ludwig A, Noda M, Takahashi C, RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci 10, 838– 845 (2007). 17558399 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    α-secretase cleavage of APP precludes β-cleavage, minimizing sAPPβ generation and subsequent Aβ production.

    “Cleavage by α-secretase precludes β-cleavage of APP, minimizing sAPPβ generation and subsequent Aβ production.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Neuronal and cell culture experiments were typically performed with three biological replicates and three technical replicates per condition.

    “Neuronal and cell culture experiments were typically performed with three biological replicates and three technical replicates per condition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Final numbers of samples analyzed for each experiment were determined by power analysis.

    “Final numbers of samples analyzed for each experiment were determined by power analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Loss of GDE2 results in reduced α-secretase cleavage of APP and a marked shift towards β-secretase APP processing.

    “Thus, loss of GDE2 results in reduced α-secretase cleavage of APP and a marked shift towards β-secretase APP processing.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • May combine two claims.

    Interpretationown data

    GDE2 functions in neurons to promote α-secretase activity and maintain the physiological balance of APP processing.

    “These observations suggest that GDE2 functions in neurons to promote α-secretase activity and to maintain the physiological balance of APP processing.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Extensive validation of antibodies against human GDE2 was performed to ensure specificity, and two different antibodies were used to ensure reproducibility.

    “Extensive validation of antibodies against human GDE2 was performed to ensure specificity, and two different antibodies were used to ensure reproducibility.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Regions of interest for each section were randomly selected for analysis and quantification.

    “regions of interest (ROIs) for each section were randomly selected for analysis and quantification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Longer Aβ peptides (≥Aβ42) are more prone to aggregation of toxic Aβ-species.

    “It is widely accepted that longer Aβ peptides (≥Aβ42) are more prone to aggregation of toxic Aβ-species (43, 44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Haass C, Selkoe DJ, Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8, 101– 112 (2007). 17245412 source
    • cites [44] Benilova I, Karran E, De Strooper B, The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15, 349– 357 (2012). 22286176 source

  • May combine two claims.

    Interpretationown data

    GDE2 is required for neuronal ADAM10 α-secretase activity, and loss of GDE2 results in a switch from non-amyloidogenic APP processing to increased β-secretase cleavage of APP in mice.

    “Taken together, this set of experiments suggests that GDE2 is required for neuronal ADAM10 α-secretase activity, and that loss of GDE2 results in a switch from non-amyloidogenic APP processing to increased β-secretase cleavage of APP in mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.
    • Rests on an assumption: Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

  • May combine two claims.

    Interpretationown data

    The amount of membrane-tethered RECK is increased in AD coincident with GDE2 intracellular accumulation, reinforcing that GDE2 activity and RECK release are disrupted in AD.

    “Thus, the amount of membrane-tethered RECK is increased in AD coincident with GDE2 intracellular accumulation, reinforcing the notion that GDE2 activity and RECK release is disrupted in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The GDE2-RECK-ADAM10 mechanism identified in mouse models and cultured neurons operates in the human AD brain.
    • Rests on an assumption: Postmortem human brain tissue protein levels and distributions reflect the antemortem state relevant to AD.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All experiments were blinded to investigators where possible.

    “All experiments were blinded to investigators where possible.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    GDE2 accumulation is not broadly observed across neurodegenerative diseases and shows some specificity to AD.

    “suggesting that GDE2 accumulation is not broadly observed across neurodegenerative diseases and shows some specificity to AD (Figure 1D, Figure S4, Table S1, Datafile S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    hGDE2 neuronal accumulation precedes profound cortical degeneration in AD and appears to increase with disease severity.

    “Thus, hGDE2 neuronal accumulation precedes profound cortical degeneration in AD and appears to increase with disease severity (Figure S4, Datafile S1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Neurons with GDE2 accumulations were averaged from a minimum of 7 sections per patient to ensure adequate sampling.

    “Neurons with GDE2 accumulations were averaged from a minimum of 7 sections per patient to ensure adequate sampling.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Statistical analysis was performed on the raw data.

    “Statistical analysis was performed on the raw data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All experiments were performed with at least 3 biological replicates per condition, with cell culture experiments having 3 technical replicates per biological replicate.

    “All experiments were performed with at least 3 biological replicates per condition, with cell culture experiments having 3 technical replicates per biological replicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Human sample cohorts were batch processed at the same time to minimize variability.

    “Human sample cohorts were batch processed at the same time to minimize variability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Confocal images were acquired using the same settings for all images acquired within the same experiment.

    “Confocal images were acquired on a Zeiss LSM 700 microscope using the same settings for all images acquired within the same experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All image contrast and brightness adjustments were made equally between experimental groups.

    “All image contrast and brightness adjustments were made equally between experimental groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All extracts prepared from human tissue were surveyed by Western blot to ensure minimal protein degradation.

    “All extracts prepared from human tissue were surveyed by Western blot to ensure minimal protein degradation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Images were acquired using the same settings for all images acquired within the same experiment.

    “Images were acquired on a Zeiss Axio Imager microscope using the same settings for all images acquired within the same experiment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The same amount of protein was loaded for each separate treatment.

    “The same amount of protein was loaded for each separate treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All data points were included in the analyses and no outliers were excluded.

    “All data points were included in the analyses and no outliers were excluded.”
    Quote in the paperNot a substantial claim
58 of 58

  • The paper relies on this without support.

    The GDE2-RECK-ADAM10 mechanism identified in mouse models and cultured neurons operates in the human AD brain.

    “These observations, viewed through the lens of our mechanistic studies, identified GDE2 as an important regulator of RECK surface expression, and propose that increased plasma membrane RECK and the inhibition of ADAM10 α-secretase function are plausible mechanisms that contribute to AD pathogenesis.”

  • The paper relies on this without support.

    Postmortem human brain tissue protein levels and distributions reflect the antemortem state relevant to AD.

    “we examined GDE2 expression in brain sections from patients with AD and healthy controls using two separate validated antibodies”

  • The paper relies on this without support.

    The Gde2−/− and APP/PS1;Gde2−/− mouse models faithfully model the GDE2 loss and APP processing changes in human AD.

    “Gde2−/− mice phenocopy GDE2-RECK abnormalities in the brain of patients with AD in that they lack GDE2 activity and exhibit increased amounts of membrane-tethered surface RECK”

  • The paper relies on this without support.

    Changes in sAPPα and sAPPβ levels in the models are attributable to altered α-secretase and β-secretase cleavage of APP, respectively.

    “Thus, loss of GDE2 results in reduced α-secretase cleavage of APP and a marked shift towards β-secretase APP processing.”

  • The paper relies on this without support.

    Membrane-tethered RECK is the functionally relevant pool that inhibits ADAM10 in vivo.

    “Surface biotinylation studies in cultured cortical neurons verify that there is a robust increase of plasma membrane RECK in absence of GDE2”

  • The paper relies on this without support.

    The Reck siRNA knockdown is specific and does not have off-target effects on APP processing.

    “Compared to control unrelated siRNAs, addition of siRNA targeting Reck resulted in an approximately 75% reduction of RECK protein expression”

  • The paper relies on this without support.

    The CD2RECK construct mimics endogenous membrane-tethered RECK in its inhibition of ADAM10.

    “CD2RECK is expressed at the correct molecular weight, traffics to neuronal plasma membrane and fails to be released by GDE2”

  • The paper relies on this without support.

    The amyloidogenic pathway is pathogenic and the non-amyloidogenic pathway is protective.

    “shift APP cleavage from the pathogenic amyloidogenic pathway to the protective non-amyloidogenic pathway”

  • The paper relies on this without support.

    Aβ peptides contribute to AD pathophysiology.

    “mitigate AD pathophysiologies”
9 of 9

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Authors
Nakamura, M., Li, Y., Choi, B.-R., Matas-Rico, E., Troncoso, J., Takahashi, C., & Sockanathan, S.
Affiliations
  • Johns Hopkins University (US)
  • The Netherlands Cancer Institute (NL)
  • Kanazawa University (JP)
Corresponding author
Sockanathan, Shanthini
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-03-17
Volume
13
Issue
585
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.abe6178
PMC
PMC8085789
OpenAlex
W3138745382
Cited by
38
References
58
Citations by year
2026: 3 · 2025: 9 · 2024: 15 · 2023: 4 · 2022: 6 · 2021: 1
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (5T32GM08752, F31AG056088, RO1AG062671, P30AG066507, 90068104)
  • American Federation for Aging Research (90068104)
  • This (5T32GM08752)
  • American Foundation for Aging Research (F31AG056088)
  • Alzheimer’s Disease Research Center, Emory University (RO1AG062671)
  • Johns Hopkins University (NIA P30AG066507)
  • Johns Hopkins Alzheimer’s Disease Research Center Pilot Project Award
  • Johns Hopkins Innovation Award
  • Johns Hopkins President’s Frontier Finalist Award
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
RECK, ADAM10, amyloid precursor protein, alpha-secretase, APP processing, amyloid-beta, Alzheimer's disease, GPI-anchored proteins, membrane shedding, therapeutic target
MeSH terms
ADAM10 Protein, Alzheimer Disease, Humans, Membrane Proteins, Neurons, Phosphoric Diester Hydrolases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, GPI-Linked Proteins

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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