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Cited by 88Alzheimer's disease research and treatmentsCellular transport and secretionNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index; 2 of the 49 sources its claims cite were checked for support.

GGA1 Is Expressed in the Human Brain and Affects the Generation of Amyloid β-Peptide

Open access
Wahle, Tina, Thal, Dietmar R., Sastre, Magdalena, Rentmeister, Andrea, Bogdanovic, Nenad, Famulok, Michael, Heneka, Michael T., Walter, Jochen·2006·The Journal of Neuroscience
DOI 10.1523/jneurosci.1982-06.2006PMC PMC6674839
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Abstract

The β-amyloid peptide (Aβ) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the β-amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. BACE1 cleaves APP at the N terminus of the Aβ domain, generating a membrane-bound C-terminal fragment (CTF-β) that can be subsequently cleaved by γ-secretase within the transmembrane domain to release Aβ. Because BACE1 initiates Aβ generation, it represents a potential target molecule to interfere with Aβ production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, γ-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-β generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Aβ. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and Aβ generation. Thus, GGA proteins might be involved in the pathogenesis of AD.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

GGA1 is expressed preferentially in human brain neurons and in plaque-associated activated microglia, and its levels are reduced in Alzheimer disease brains. In cultured cells, GGA1 modulates APP processing and Aβ generation, likely via altered subcellular trafficking of BACE1 rather than direct APP binding.

Key findings

  • GGA1 was mainly neuronal in control and AD brains, with variable expression across neuron types; GGA1-positive astrocytes were more frequent in AD cases, and activated microglia bordering cored plaques expressed GGA1, whereas amyloid material itself did not stain for GGA1.
  • GGA1 levels were significantly decreased in AD brains by ~40% (p < 0.05), while BACE1 was slightly increased and presenilin 1 and APP were not significantly changed.
  • Overexpression of GGA1 full-length or dominant-negative reduced Aβ secretion; GGA1 dominant-negative also reduced total APPs and APPs-α, and both variants decreased CTF-β levels. RNAi-mediated suppression of GGA1 increased secreted Aβ by ~30% (p < 0.05), with GGA1 mRNA decreased by 74%.
  • GGA1 colocalized with APP but did not directly bind APP by pull-down or surface plasmon resonance; BACE1 cytoplasmic domain bound GGA1, and total cellular BACE1 activity was not affected by GGA1 expression.

Methods

  • Human autopsy brain tissue from control and AD cases was analyzed by immunohistochemistry, double-label immunohistochemistry, and Western immunoblotting; brain material analysis used exact logistic regression controlled for age, gender, Braak stage, and postmortem intervals.
  • HEK293 and SH-SY5Y cells were transfected with APP695 alone or with GGA1 full-length or dominant-negative variants; H4 cells were transfected with GGA1-specific siRNAs or nontargeting controls.
  • Analyses included metabolic labeling/pulse-chase, immunoprecipitation, immunocytochemistry, GST pull-down assays, surface plasmon resonance, BACE1 activity assay, and real-time PCR; quantitations used three independent experiments (n = 3) with Student’s t test (*p < 0.05; p < 0.01).

Limitations

  • The paper states that the physiological relevance of decreased GGA1 expression on APP processing and Aβ generation is unclear in the absence of GGA1 knock-out mice.
  • The paper states that additional GGA-dependent mechanisms, such as effects via LR11/SorLa, mannose 6-phosphate receptor trafficking, or ARF/clathrin-dependent vesicle transport, could also contribute and were not fully dissected.
  • Evident from the text: functional conclusions rely mainly on cultured cell models (HEK293, SH-SY5Y, H4) with overexpression, dominant-negative, or RNAi manipulations, and the human brain data are expression/correlative rather than causal.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.1982-06.2006

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

2 of 49 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Total cellular activity of BACE1 was not affected by GGA1 expression.

    “Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular”
    • Also stated in: § GGA1 affects proteolytic processing of APP · plain
      “Because neither the maturation nor total cellular activity of BACE1 is altered by GGA1 expression”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.
  • Findingown data

    Overexpression of GGA1 full-length or dominant-negative variant decreased CTF-β levels in APP-overexpressing cells.

    “Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-␤ generation.”
    • Also stated in: § GGA1 affects proteolytic processing of APP · plain
      “Compared with cells overexpressing APP alone, cells coexpressing GGA1 FL or GGA1 DN revealed decreased levels of CTF-␤”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.
  • Findingown data

    GGA1 was detected in activated microglia surrounding amyloid plaques in AD brains.

    “GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains.”
    • Also stated in: § Expression of GGA1 in human control and AD brain · boosted
      “In cored plaques, activated microglial cells, bordering the amyloid core, exhibited GGA1 as demonstrated by the colocalization of the microglial-associated epitope CD68 and GGA1”
    • Also stated in: § Discussion · plain
      “Interestingly, senile plaque-associated microglial cells also express GGA1, whereas the amyloid material itself did not stain positive for GGA1.”
    Quote in the paperNot a substantial claim
  • Findingown data

    RNAi-mediated suppression of GGA1 increased secreted Aβ by approximately 30% (p < 0.05).

    “The RNAi-mediated suppression of GGA1 significantly increased levels of secreted A␤ of ϳ30% ( p Ͻ 0.05) compared with control cells”
    • Also stated in: § Abstract · plain
      “Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of A␤.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.
    • Rests on an assumption: The siRNA-mediated knockdown of GGA1 is specific and without relevant off-target effects.
  • Findingown data

    GGA1 does not directly bind APP.

    “However, no significant binding between GGA1 and APP was observed”
    • Also stated in: § Colocalization of GGA1 and APP in cultured cells · plain
      “Consistent with the results from pull-down assays, no binding of APP to GGA1 was detected by both methods”
    • Also stated in: § Colocalization of GGA1 and APP in cultured cells · hedged
      “Together, these data indicate that GGA1 colocalizes with, but does not directly bind to, APP.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.
  • Probably not a substantial claim. 30
  • It may state two separate claims as one. 25

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    GGA proteins are monomeric adaptor proteins that mediate transport of cargo proteins between the TGN and endosomes.

    “GGA proteins are monomeric adaptor proteins that mediate transport of cargo proteins between the TGN and endosomes”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Dell'Angelica et al., 2000 source

      The Discussion describes GGAs as adaptor-related proteins that are not part of AP complexes, and the Introduction links them to protein trafficking at the TGN. But the Discussion describes their association with endosomal structures only as a possibility; the paper does not establish that GGAs mediate cargo transport between the TGN and endosomes. It also does not explicitly establish that they are monomeric. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Hirst et al., 2000 source

      The Abstract and Discussion support a role for GGAs in trafficking proteins from the TGN toward the vacuole or lysosome, and report that GGA1 and GGA2 are not associated with each other or AP-1. The Discussion does not establish monomeric adaptor status and explicitly leaves open whether the trafficking step runs from the late Golgi to a prevacuolar endosomal compartment. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Doray et al., 2002 source

  • It may state two separate claims as one.

    Findingown data

    The presubicular region, the temporal isocortex (TI) and the CA4 region exhibit lower levels of GGA1.

    “The presubicular region, the temporal isocortex (TI) and the CA4 region exhibit lower levels of GGA1.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The neuropil of the TI was less densely stained.

    “The neuropil of the TI was less densely stained.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    GGA1 expression varied in different types of nerve cells and different brain areas.

    “Different types of nerve cells as well as different areas of the brain exhibited varying levels of GGA1.”
    • Also stated in: § Expression of GGA1 in human control and AD brain · plain
      “Similarly, the cytoplasmic expression of GGA1 in different neurons varied.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    BACE1 levels were slightly increased in AD brains.

    “Consistent with previous data (Holsinger et al., 2002;Yang et al., 2003;Sastre et al., 2006), levels of BACE1 were slightly increased in AD brains”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Holsinger et al., 2002 source
    • cites Yang et al., 2003 source
    • cites Sastre et al., 2006 source

  • It may state two separate claims as one.

    Findingown data

    GGA1 full-length overexpression did not significantly alter total APPs secretion, whereas GGA1 dominant-negative overexpression significantly decreased total APPs secretion.

    “Although overexpression of GGA1 FL did not significantly alter the secretion of total APPs, cells overexpressing GGA1 DN secreted significantly lower levels of APPs”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.

  • It may state two separate claims as one.

    Findingown data

    We detected colocalization and copurification of BACE1 with AP-1-positive vesicles.

    “We detected colocalization and copurification of BACE1 with AP-1-positive vesicles (data not shown), known to mediate the direct transport of cargo proteins from TGN to endosomes (Diaz and Pfeffer, 1998;Meyer et al., 2000).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Presenilin 1 and APP levels were not significantly changed in AD brains.

    “Levels of presenilin 1, a critical component of the ␥-secretase complex, and that of APP were not significantly changed”
    Quote in the paperNot a substantial claim

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

    Findingown data

    These astrocytes often occur without association to senile plaques.

    “Note that these astrocytes often occur without association to senile plaques (A, B, arrowheads).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The hippocampal formation of an AD brain exhibits a pattern similar to normal human brain.

    “The hippocampal formation of an AD brain exhibits a pattern similar to normal human brain (see also supplemental Fig. 2, available at www.jneurosci.org as supplemental material).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Neither GGA1 full-length nor GGA1 dominant-negative expression affected total protein secretion.

    “Neither GGA1 FL nor GGA1 DN affected total protein secretion, indicating a selective effect on secretion and/or proteolytic processing of APP”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.

  • It may state two separate claims as one.

    Findingown data

    Microglial cells and oligodendrocytes contained no anti-GGA1-immunopositive material, whereas some astrocytes in the subpial zone of the molecular layer showed cytoplasmic GGA1.

    “Microglial cells and oligodendrocytes contained no anti-GGA1-immunopositive material, whereas some astrocytes in the subpial zone of the molecular layer showed cytoplasmic GGA1”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Dentate gyrus granule cells did not exhibit significant GGA1 reactivity, CA4 neurons were strongly positive, and CA1/subiculum pyramidal cells showed mild GGA1 immunodecoration.

    “Although dentate gyrus granule cells did not exhibit significant GGA1 reactivity, CA4 neurons were strongly positive and CA1/subiculum pyramidal cells showed a mild GGA1 immunodecoration”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    GGA1 dominant-negative expression markedly reduced APPs-α secretion, whereas GGA1 full-length expression did not significantly affect APPs-α secretion.

    “In cells expressing GGA1 DN, secretion of APPs-␣ was also markedly reduced, whereas GGA1 FL expression did not significantly affect APPs-␣ secretion compared with cells overexpressing APP alone”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.

  • It may state two separate claims as one.

    Findingown data

    GGA1-positive astrocytes were mainly found in neocortical and allocortical parts of the brain, and subcortical nuclei less frequently exhibited GGA1-positive astrocytes.

    “GGA1-positive astrocytes were mainly found in neocortical and allocortical parts of the brain.Subcortical nuclei less frequently exhibited GGA1-positive astrocytes”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In cored plaques, the amyloid core was rimmed by GGA1-positive cells, and in the neighborhood of the plaque, non-neuronal GGA1-positive cells were seen.

    “In cored plaques, the amyloid core (c) was rimmed by GGA1-positive cells (arrows), and in the neighborhood of the plaque, non-neuronal GGA1-positive cells were seen (arrowhead).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    APP is expressed in its mature and immature form.

    “APP is expressed in its mature (m) and immature (im) form.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Three neurons in the CA1-subiculum area exhibited similar levels of GGA1.

    “Three neurons in the CA1-subiculum area exhibited similar levels of GGA1.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    GGA1 affects the proteolytic processing of APP and decreases secretion of Aβ.

    “Figure 6 . Figure6.GGA1 affects the proteolytic processing of APP and decreases secretion of A␤.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Aβ is generated by sequential cleavage of APP by β-secretase and γ-secretase.

    “The ␤-amyloid peptide (A␤) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the ␤-amyloid precursor protein (APP) by ␤-secretase (BACE1) and ␥-secretase.”
    • Also stated in: § Introduction · plain
      “A␤ derives from the ␤-amyloid precursor protein (APP) by proteolytic processing involving sequential cleavages by ␤-secretase and ␥-secretase”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Selkoe, 2001 source
    • cites Walter et al., 2001a

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

    • cites Annaert and de Strooper, 2002 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    BACE1 cleaves APP at the N terminus of the Aβ domain, generating CTF-β that can be subsequently cleaved by γ-secretase to release Aβ.

    “BACE1 cleaves APP at the N terminus of the A␤ domain, generating a membrane-bound C-terminal fragment (CTF-␤) that can be subsequently cleaved by ␥-secretase within the transmembrane domain to release A␤.”
    • Also stated in: § Introduction · plain
      “␤-secretase was identified as the aspartyl protease ␤-site APP cleaving enzyme-1 (BACE1) that cleaves APP at the N terminus of the A␤ domain”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hussain et al., 1999 source
    • cites Sinha et al., 1999 source
    • cites Yan et al., 1999 source

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

    Interpretationreasoning

    GGAs could also affect APP metabolism indirectly by regulating the transport of other proteins.

    “In addition, GGAs could also affect APP metabolism indirectly by regulating the transport of other proteins.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Exact logistic regression analysis controlled for age, gender, Braak stage, and postmortem intervals.

    “For brain material, exact logistic regression analysis controlled for age, gender, and Braak stage, and postmortem intervals were performed with LogXact 5.0”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The stage of neurofibrillary pathology was determined according to Braak and Braak (1991).

    “The stage of neurofibrillary pathology was determined according to Braak and Braak (1991)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Braak and Braak, 1991 source

  • Probably not a substantial claim.

    Study design and conductcitation

    The neuropathological diagnosis of definite AD was determined by using widely accepted consensus.

    “The neuropathological diagnosis of definite AD was determined by using widely accepted consensus (The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, 1997).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease, 1997

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

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

    Study design and conductnone given

    For quantitations, three independent experiments (n=3) were performed.

    “For quantitations, three independent experiments (n ϭ 3) were performed.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    From the cell surface, both APP and BACE1 could be internalized into endosomal compartments, in which APP could preferentially be cleaved by β-secretase.

    “From the cell surface, both APP and BACE1 could be internalized into endosomal compartments, in which APP could preferentially be cleaved by ␤-secretase.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    GGA proteins interact with the cytoplasmic domain of BACE1 in a phosphorylation-state-dependent manner and regulate the endocytic trafficking of this protease.

    “GGA proteins have been shown to interact with the cytoplasmic domain of BACE1 in a phosphorylation-state-dependent manner and to regulate the endocytic trafficking of this protease (He et al., 2002(He et al., , 2003(He et al., , 2005;;von Arnim et al., 2004;Wahle et al., 2005).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites He et al., 2002

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

    • cites von Arnim et al., 2004 source
    • cites Wahle et al., 2005 source

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

    Interpretationreasoning

    It is plausible that trafficking and metabolism of APP could be affected when LR11/SorLA is complexed with GGA proteins.

    “it is plausible that trafficking and metabolism of APP could be affected when LR11/SorLA is complexed with GGA proteins.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    GGA1 knockdown was confirmed by Western immunoblotting and real-time PCR.

    “GGA1 knockdown was confirmed by Western immunoblotting using polyclonal GGA1 antibody (Abcam), as well as by real-time PCR (Bio-Rad, Hercules, CA) using specific probes.”
    • Also stated in: § GGA1 affects proteolytic processing of APP · plain
      “The cells transfected with GGA1 siRNAs showed decreased expression of endogenous GGA1 protein compared with control cells”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The siRNA-mediated knockdown of GGA1 is specific and without relevant off-target effects.

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

    Interpretationreasoning

    GGA-dependent changes in M6PR trafficking could also contribute to the observed changes in APP processing.

    “Thus, GGAdependent changes in M6PR trafficking could also contribute to the observed changes in APP processing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    AP-1-positive vesicles mediate direct transport of cargo proteins from TGN to endosomes.

    “known to mediate the direct transport of cargo proteins from TGN to endosomes (Diaz and Pfeffer, 1998;Meyer et al., 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Diaz and Pfeffer, 1998

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

    • cites Meyer et al., 2000 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    LR11/SorLA interacts with APP and affects its subcellular localization and proteolytic processing.

    “It was demonstrated that LR11/SorLA interacts with APP and affects its subcellular localization and proteolytic processing (Andersen et al., 2006;Offe et al., 2006;Spoelgen et al., 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Andersen et al., 2006 source
    • cites Offe et al., 2006 source
    • cites Spoelgen et al., 2006 source

  • Probably not a substantial claim.

    Premisecitation

    Expression of M6PR has been shown to affect Aβ generation.

    “and expression of this receptor has also been shown to affect A␤ generation (Mathews et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mathews et al., 2002 source

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

    Interpretationreasoning

    Expression of GGA1 variants might also impair vesicular transport by interfering with ARF- or clathrin-dependent mechanisms that could also alter APP processing.

    “Therefore, expression of GGA1 variants might also impair vesicular transport by interfering with ARF-or clathrin-dependent mechanisms that could also alter APP processing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisereasoning

    BACE1 initiates Aβ generation.

    “Because BACE1 initiates A␤ generation, it represents a potential target molecule to interfere with A␤ production in therapeutic strategies for AD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Because GGA1 could shuttle BACE1 from endosomal compartments to other compartments, including the TGN, this could reduce the amount of BACE1 in endosomes and thus β-secretory cleavage of APP.

    “Because GGA1 could shuttle BACE1 from endosomal compartments to other compartments, including the TGN, this could reduce the amount of BACE1 in endosomes and thus ␤-secretory cleavage of APP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    GGA proteins are adaptor proteins that, in addition to binding to cargo proteins, also interact with the small GTPase ARF, clathrin, and additional proteins involved in vesicle assembly and targeting.

    “In addition, GGA proteins are adaptor proteins that, in addition to binding to cargo proteins, also interact with the small GTPase ARF, clathrin, and additional proteins involved in vesicle assembly and targeting (Bonifacino, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bonifacino, 2004 source

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

    Interpretationreasoning

    GGA proteins could also affect the proteolytic processing of APP, independent of a direct interaction with BACE1.

    “GGA proteins could also affect the proteolytic processing of APP, independent of a direct interaction with BACE1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    The GGA1 dominant-negative variant interferes with transport of cargo protein from TGN to endosomal/lysosomal compartments.

    “The GGA1 DN variant has been shown to interfere with transport of cargo protein from TGN to endosomal/lysosomal compartments (Puertollano et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Puertollano et al., 2001 source

  • It may state two separate claims as one.

    Interpretationown data

    APP is unlikely to represent a cargo protein of GGAs and its subcellular trafficking is unlikely to be regulated by direct binding to GGAs.

    “Therefore, it is unlikely that APP represents a cargo protein of GGAs and that its subcellular trafficking is regulated by direct binding to GGAs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationreasoning

    Expression of GGA1 DN might lead to reduced BACE1 levels in endosomal/lysosomal compartments and thereby decrease β-secretory processing of APP and Aβ generation in this compartment.

    “In that case, expression of GGA1 DN might lead to reduced BACE1 levels in endosomal/lysosomal compartments and thereby decrease ␤-secretory processing of APP and A␤ generation in this compartment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: GGA1 DN acts as a dominant-negative inhibitor of GGA1 function.

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

    Premisecitation

    GGA1 mRNA has been detected in brain tissue.

    “GGA1 mRNA has been detected in brain tissue (Boman et al., 2000), but expression of the corresponding protein has not been demonstrated thus far.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boman et al., 2000 source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    Additional GGA-dependent mechanisms, e.g., interaction with LR11/SorLa or M6P receptor, could also affect trafficking the proteolytic processing of APP.

    “Additional GGA-dependent mechanisms, e.g., interaction with LR11/SorLa or M6P receptor (?), could also affect trafficking the proteolytic processing of APP (see Discussion).”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    GGA1 is detected in two forms, likely representing phosphorylated and nonphosphorylated variants.

    “GGA1 is detected in two forms, likely representing phosphorylated (GGA1) and nonphosphorylated (GGA1*) variants.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The GGA1 DN variant could decrease this transport route, also resulting in decreased endosomal BACE1.

    “The GGA1 DN variant could therefore decrease this transport route, also resulting in decreased endosomal BACE1.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: GGA1 DN acts as a dominant-negative inhibitor of GGA1 function.

  • It may state two separate claims as one.

    Interpretationcitation

    Both APP and BACE1 could be endocytosed from the cell surface into endosomal compartments.

    “Both proteins could be endocytosed from the cell surface into endosomal compartments (2).”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    GGA1 is present in two forms, which might represent the phosphorylated and nonphosphorylated species.

    “GGA1 is present in two forms, which might represent the phosphorylated and nonphosphorylated (*) species.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    GGA1 might also facilitate the direct transport of BACE1 from the TGN to endosomal compartments.

    “In addition, GGA1 might also facilitate the direct transport of BACE1 from the TGN to endosomal compartments.”
    Quote in the paperNot a substantial claim
49 of 49

  • The paper relies on this without support.

    GGA1 protein expression in the brain had not been demonstrated before this study.

    “GGA1 mRNA has been detected in brain tissue (Boman et al., 2000), but expression of the corresponding protein has not been demonstrated thus far.”
    “Because the expression of GGA1 in the brain has not been characterized thus far, we first performed immunohistochemical experiments using human control and AD brains.”

  • The paper relies on this without support.

    The function of GGAs in the nervous system or their involvement in neurodegenerative diseases was not known before this study.

    “Although the function of GGAs in cultured peripheral cells is well established, their roles in the nervous system or an involvement in neurodegenerative diseases is not known.”
    “The role of GGA proteins in the nervous system is not known.”

  • The paper relies on this without support.

    Cultured cell models (HEK293, SH-SY5Y, H4) reflect the relevant APP processing and Aβ generation in human neurons or brain.

    “By analyzing the functional role of GGA1 in cultured cells with endogenous ␤-secretase activity, we found that GGA1 alters the proteolytic processing of APP and the secretion of APPs and A␤.”
    “For functional investigations on the role of GGA proteins on proteolytic processing of APP, we used mainly HEK293 cells that endogenously express low levels of ␤-secretase activity”

  • The paper relies on this without support.

    The siRNA-mediated knockdown of GGA1 is specific and without relevant off-target effects.

    “For siRNA-mediated knockdown of GGA1, a mixture of three different siRNA oligonucleotides was used”
    “The RNAi-mediated suppression of GGA1 significantly increased levels of secreted A␤”

  • The paper relies on this without support.

    GGA1 DN acts as a dominant-negative inhibitor of GGA1 function.

    “GGA1 DN is truncated after amino acid 247 and lacks parts of the GAT domain as well as the hinge and ␥-ear domains.”

  • The paper relies on this without support.

    GGA1-specific siRNA suppresses GGA1 without off-target effects on Aβ secretion.

    “H4 cells were transfected with nontargeting (ctr.) or GGA1-specific siRNAs.”
6 of 6

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Metadata

Authors
Wahle, T., Thal, D. R., Sastre, M., Rentmeister, A., Bogdanovic, N., Famulok, M., Heneka, M. T., & Walter, J.
Affiliations
  • University of Bonn (DE)
  • Institut für Neuropathologie (DE)
Corresponding author
Walter, Jochen
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2006-12-06
Volume
26
Issue
49
Pages
12838-12846
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1982-06.2006
PMC
PMC6674839
OpenAlex
W2067991812
Semantic Scholar
d2a114551e24c0b9ddfa67ab026014ba6934bdd7
Cited by
88
References
57
Citations by year
2026: 2 · 2024: 2 · 2023: 6 · 2022: 1 · 2021: 8 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 10 · 2013: 3 · 2012: 10
FWCI
2.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
GGA1, amyloid-beta, APP processing, BACE1, gamma-secretase, Alzheimer's disease, intracellular trafficking, microglia, neurons, Golgi apparatus, dominant-negative mutant, RNAi knockdown
MeSH terms
Aged, Aged, 80 and over, Brain, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Protein Processing, Post-Translational, Amyloid beta-Peptides, ADP-Ribosylation Factors, Adaptor Proteins, Vesicular Transport

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.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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