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Cited by 49Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsCellular transport and secretion

LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking

Open access
Ranganathan, S., Noyes, N. C., Migliorini, M., Winkles, J. A., Battey, F. D., Hyman, B. T., Smith, E., Yepes, M. +2 more·2011·Journal of Neuroscience
DOI 10.1523/jneurosci.5065-10.2011PMC PMC3189500
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Abstract

We have identified a novel low-density lipoprotein (LDL) receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons. The LRAD3 gene encodes an ∼50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW-domain-containing proteins. Immunohistochemical analysis of mouse brain reveals LRAD3 expression in the cortex and hippocampus. In the mouse hippocampal-derived cell line HT22, LRAD3 partially colocalizes with amyloid precursor protein (APP) and interacts with APP as revealed by coimmunoprecipitation experiments. To identify the portion of APP that interacts with LRAD3, we used solid-phase binding assays that demonstrated that LRAD3 failed to bind to a soluble APP fragment (sAPPα) released after α-secretase cleavage. In contrast, C99, the β-secretase product that remains cell associated, coprecipitated with LRAD3, confirming that regions within this portion of APP are important for associating with LRAD3. The association of LRAD3 with APP increases the amyloidogenic pathway of APP processing, resulting in a decrease in sAPPα production and increased Aβ peptide production. Pulse-chase experiments confirm that LRAD3 expression significantly decreases the cellular half-life of mature APP. These results reveal that LRAD3 influences APP processing and raises the possibility that LRAD3 alters APP function in neurons, including its downstream signaling.

AI snapshot

Written from the paper’s full text.

TL;DR

LRAD3 is a novel neuronal LDL receptor family member that binds APP via the C99 region and shifts APP processing toward the amyloidogenic pathway. Expressing LRAD3 decreases sAPPα, increases Aβ40, and shortens mature APP half-life.

Key findings

  • LRAD3 encodes a ~50 kDa type I transmembrane receptor of 345 amino acids with three LDLa repeats, a conserved dileucine internalization motif, and two polyproline motifs; it is expressed in brain cortex and hippocampus, including CA1 and dentate gyrus.
  • LRAD3 co-localizes and co-immunoprecipitates with APP; it binds C99 but not sAPPα, indicating the APP interaction determinant lies within the C99 fragment rather than the α-secretase-released ectodomain.
  • LRAD3 expression decreases sAPPα and significantly increases Aβ40 production in CHO 13-5-1 cells, and pulse-chase experiments show APP695 half-life falls from 2.6 h in control HEK 293 cells to 1.3 h with LRAD3.
  • LRAD3 internalizes ligand slowly compared with LRP1-β (endocytic rate constant ke = 0.0038 min−1 vs 0.0308 min−1, ~8-fold slower), does not bind RAP with high affinity, and does not effectively co-immunoprecipitate with Fe65.

Methods

  • The study used EST database screening, cDNA cloning/sequencing, Northern blotting, immunoblotting, immunohistochemistry, immunofluorescence, flow cytometry, and endocytic/internalization assays.
  • Cell and tissue models included mouse brain extracts, primary cortical neurons, HT22 mouse hippocampal cells, COS1 cells, LRP1-deficient CHO 13-5-1 cells, and HEK 293 cells, with LRAD3 and/or APP constructs expressed by transfection.
  • APP interaction and processing were assessed by co-immunoprecipitation, solid-phase binding assays, Aβ40 ELISA, and [35S]methionine/cysteine pulse-chase; significance was analyzed by Student’s t-test with p<0.05.

Limitations

  • Stated: the mechanism by which LRAD3 modulates APP trafficking and processing is not known; the ligands for LRAD3 are unknown, and whether LRP ligands such as activated α2M, uPA, apoE, or tPA bind LRAD3 remains to be determined.
  • Stated: not all neurons in culture appeared to express LRAD3, and Fe65 did not effectively associate with LRAD3 despite the polyproline motifs.
  • Evident from the text: most mechanistic data rely on transfected cell lines and overexpression systems, and no in vivo causal test of LRAD3 in Aβ deposition or Alzheimer’s disease progression is reported.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.5065-10.2011

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

10 of 42 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    LRP1 is known to increase production of Aβ peptide.

    “Since LRP1 is known to increase the production of Aβ peptide (Ulery et al., 2000; Pietrzik et al., 2002), LRP1-deficient cell lines were chosen to eliminate any possible contribution of LRP1 to this process.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Ulery et al., 2000 source
    • cites Pietrzik et al., 2002 source
  • Findingcitation

    The cytoplasmic domain of LRAD3 contains two polyproline sequences, SPPSY and PPPPY.

    “The cytoplasmic domain of LRAD3 also contains two polyproline sequences, SPPSY, and PPPPY, which represent consensus sequences that are recognized by WW domain containing proteins (Sudol, 1996; Pawson and Scott, 1997).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Sudol, 1996 source

      Section 2.2 identifies XPPXY as a preliminary WW-domain binding consensus and reports PPPPY as a sequence in two WW-domain ligands. Both SPPSY and PPPPY fit that consensus, but the paper does not establish that either sequence occurs in the cytoplasmic domain of LRAD3. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Pawson and Scott, 1997 source
  • Findingcitation

    The cytoplasmic domain of LRAD3 contains a conserved dileucine motif.

    “Instead, the cytoplasmic domain of LRAD3 contains a conserved dileucine motif which has been demonstrated to mediate endocytosis and sorting of many receptors, including CD3 (Letourneur and Klausner, 1992), IgG Fc receptors (Hunziker and Fumey, 1994), the IL-6 receptor (Dittrich et al., 1996), and CD44 (Sheikh and Isacke, 1996).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Letourneur and Klausner, 1992 source
    • cites Hunziker and Fumey, 1994 source
    • cites Dittrich et al., 1996 source
  • Findingown data

    The half-life of APP695 in control HEK 293 cells is 2.6 h.

    “The half life of APP695 in control 293 cells was 2.6 h, a value that is consistent with prior studies (Borg et al., 1998).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Borg et al., 1998 source

      The X11α Coexpression section reports an APP half-life of approximately 2 hours in HEK 293 cells, and the Experimental Procedures specify that the study used APP695. This supports a similar control-cell half-life, but the source does not report the cited value of 2.6 hours. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingcitation

    LRAD3 lacks the EGF and β-propeller domains found in extracellular portions of LDL receptor family members.

    “LRAD3 also lacks the EGF and β-propeller domains that are found in the extracellular portions of LDL receptor family members which are important for pH-induced uncoupling of ligands within acidic endosomal compartments (Davis et al., 1987; Mikhailenko et al., 1999; Rudenko et al., 2002).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Davis et al., 1987 source
    • cites Mikhailenko et al., 1999 source
    • cites Rudenko et al., 2002 source

      The Extracellular Domain at Endosomal pH section describes EGF-like repeats and a β-propeller in LDL-R and says the EGF precursor homology domain is required for ligand release. The Monomer description links that domain to release at acidic pH. Neither passage establishes that LRAD3 lacks these domains, so the LRAD3-specific part of the claim is unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 26

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

    Premisecitation

    Many WW domain-containing proteins are involved in regulatory or cell signaling processes.

    “The list of proteins that contain WW domains is expanding, and many of these molecules appear to be involved in regulatory or cell signaling processes (Sudol, 1996; Pawson and Scott, 1997).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Sudol, 1996 source
    • cites Pawson and Scott, 1997 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The dileucine motif mediates endocytosis and sorting of many receptors.

    “the cytoplasmic domain of LRAD3 contains a conserved dileucine motif which has been demonstrated to mediate endocytosis and sorting of many receptors, including CD3 (Letourneur and Klausner, 1992), IgG Fc receptors (Hunziker and Fumey, 1994), the IL-6 receptor (Dittrich et al., 1996), and CD44 (Sheikh and Isacke, 1996).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Letourneur and Klausner, 1992 source
    • cites Hunziker and Fumey, 1994 source
    • cites Dittrich et al., 1996 source

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

    Premisecitation

    Several ligands that interact with LRP are thought to initiate signaling events.

    “Interestingly, several ligands that are capable of interacting with LRP are also thought to initiate signaling events. These ligands include activated α2M (Misra et al., 1994), urokinase-type plasminogen activator (Nguyen et al., 1998), apolipoprotein E (Riddell et al., 1997) and tissue-type plasminogen activator (Hu et al., 2006).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Misra et al., 1994 source
    • cites Nguyen et al., 1998 source
    • cites Riddell et al., 1997 source

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

    Premisecitation

    WW domains bind to proteins containing a minimal consensus sequence of XPPXY.

    “WW domains are small modules of 35 to 40 amino acids that are characterized by four well conserved aromatic residues of which two are tryptophans, that bind to proteins containing a minimal consensus sequence of XPPXY (Bork and Sudol, 1994; Chen and Sudol, 1995).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Bork and Sudol, 1994 source
    • cites Chen and Sudol, 1995 source

      The Abstract reports that the WW domain of YAP binds ligands with a PY motif and that a preliminary XPPXY consensus is critical for binding. The claim extends that result from YAP’s WW domain to WW domains generally and omits the preliminary qualification. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    LRAD3 is a novel LDL receptor family member expressed in neurons.

    “We have identified a novel LDL receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The LRAD3 gene encodes an approximately 50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs.

    “The LRAD3 gene encodes an approximately 50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW domain containing proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the cerebellum, LRAD3 staining is particularly intense in the granular layer and is also detected in some Purkinje and molecular layer cells.

    “In the cerebellum, the staining is particularly intense in the granular layer (Fig 5G). However, LRAD3 staining is also detected in some Purkinje and molecular layer cells (Fig 5H).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The LRAD3 gene is located on chromosome 11 (11p13) and encodes a protein of 345 amino acids.

    “The LRAD3 gene, which is located on chromosome 11 (location: 11p13), encodes a protein of 345 amino acids (Fig 1A).”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Cleavage by signal peptidase is predicted to occur following serine-17, resulting in a 328 amino acid mature protein with a calculated molecular mass of 36 kDa.

    “Cleavage by signal peptidase is predicted to occur following serine-17 (Bendtsen et al., 2004), resulting in a 328 amino acid mature protein with a calculated molecular mass of 36 kDa, excluding any contribution of carbohydrates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bendtsen et al., 2004 source

  • May combine two claims.

    Findingown data

    In the hippocampus, LRAD3 is found throughout all CA layers, with more prominent staining in the CA1 layer and dentate gyrus.

    “In the hippocampus LRAD3 is found throughout all CA layers. However, the staining appears more prominent in the CA1 layer and in the dentate gyrus (DG) (Fig 5B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LRAD3-Nmyc-transfected COS1 cells bind and internalize 125I-labeled 9E10 antibody, whereas vector-transfected COS1 cells do not.

    “The results of this experiment indicate that LRAD3-Nmyc-transfected COS1 cells bound 125I-labeled 9E10 and internalized this antibody, whereas COS1 cells transfected with vector alone failed to bind or internalize 125I-9E10 (Fig. 3H, I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LRAD3 mRNA is expressed at moderate levels in heart, placenta, and kidney, but is not detected in the liver.

    “LRAD3 mRNA was expressed at moderate levels in heart, placenta, and kidney, but was not detected in the liver.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the brainstem, LRAD3 staining is evident in the pontine nuclei and the medial vestibular nucleus.

    “In the brainstem, staining is evident in both the pontine nuclei (Fig 5E) and the medial vestibular nucleus (Fig 5F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    LRAD3 contains an extracellular region composed of three LDLa ligand binding repeats, a transmembrane domain, and a large cytoplasmic domain.

    “The receptor, termed low density lipoprotein receptor class A domain containing 3 (LRAD3) (Otsuki et al., 2005), contains an extracellular region composed of three LDLa ligand binding repeats, a transmembrane domain, and a large cytoplasmic domain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Otsuki et al., 2005

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

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

    Findingown data

    A smaller size LRAD3 transcript is detected in vascular smooth muscle cells.

    “a smaller size LRAD3 transcript is detected in vascular smooth muscle cells (Fig 4B)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There are four putative phosphorylation sites and two proline-rich stretches within the cytoplasmic domain of LRAD3.

    “There are four putative phosphorylation sites and two proline-rich stretches within the cytoplasmic domain”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LRAD3 is expressed in microvascular endothelial cells and in neurons.

    “identified an uncharacterized LDLR family member that is expressed in microvascular endothelial cells and in neurons.”
    Quote in the paperSubstantial claim

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

    Findingown data

    LRAD3 is highly conserved amongst various species.

    “LRAD3 is highly conserved amongst various species (Fig 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The extracellular region of LRAD3 contains three LDL receptor class A (LDLa) repeats and two consensus sites for N-linked glycosylation.

    “The extracellular region of LRAD3 contains three LDL receptor class A (LDLa) repeats common to the LDL receptor family as well as two consensus sites for N-linked glycosylation (Fig 1A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LRAD3 is diffusely found in the cerebral cortex, with more intense staining in cortical layers II-III and V.

    “LRAD3 is diffusely found in the cerebral cortex, but the staining is more intense in the cortical layers II–III and V (Fig 5C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immunofluorescence microscopy of HT22 cells revealed a punctate staining pattern for LRAD3 and for APP.

    “Immunofluorescence microscopy of HT22 cells revealed a punctate staining pattern for LRAD3 (Fig 7D) and for APP (Fig 7E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The cytoplasmic domain of LRAD3 consists of 151 amino acids, does not contain NPXY internalization sequences, and contains a conserved dileucine motif.

    “The cytoplasmic domain of LRAD3 consists of 151 amino acids, and unlike most other members of the LDL receptor family, LRAD3 does not contain NPXY internalization sequences, but instead contains a conserved dileucine motif”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    LRAD3 contains a transmembrane domain and a 151 amino acid cytoplasmic domain.

    “LRAD3 contains a transmembrane domain and a 151 amino acid cytoplasmic domain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The three LDLa repeats in LRAD3 ectodomain are homologous to those in LRP and other LDL receptor family members, but none have the three conserved calcium-coordinating acidic residues.

    “The three LDLa repeats in the ectodomain are homologous to those found in LRP and other members of the LDL receptor family, but none have the three conserved, calcium-coordinating acidic residues that were found to encircle lysine residues present on LRP ligands (Fisher et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fisher et al., 2006 source

  • May combine two claims.

    Study design and conductown data

    LRAD3 expression in HT22 cells was confirmed by both immunoblotting and FACS analysis.

    “The expression of LRAD3 in these cells was confirmed by both immunoblotting (Fig 7A, lane 2) and FACS analysis (Fig 7, B, C).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Proline-rich stretches have been implicated in mediating protein-protein interactions.

    “which have been implicated in mediating protein-protein interactions (Cohen et al., 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cohen et al., 1995 source

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

    Premisecitation

    RAP binds tightly to most LDL receptor family members and functions as a molecular chaperone that assists in delivering the receptors to the cell surface.

    “RAP binds tightly to most LDL receptor family members and functions as a molecular chaperone that assists in delivering the receptors to the cell surface (Willnow et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Willnow et al., 1996 source

  • May combine two claims.

    Study design and conductown data

    The anti-LRAD3 antibody is specific for LRAD3 and does not cross-react with LRP1.

    “Immunoblotting experiments confirmed that the anti-LRAD3 antibody is specific for LRAD3 and does not cross-react with LRP1 (Fig 3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The determinant for interaction between APP and LRAD3 resides within the C99 fragment, not within the large ectodomain released upon α-secretase cleavage.

    “Together, these experiments reveal that the determinant for the interaction between APP with LRAD3 resides within the C99 fragment, and not within the large ectodomain that is released upon α-secretase cleavage.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The conserved dileucine motif, when present on other receptors, has been shown to mediate endocytosis.

    “which when present on other receptors has been shown to mediate endocytosis (Hamer et al., 1997; Haft et al., 1994).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hamer et al., 1997 source
    • cites Haft et al., 1994 source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Other WW-domain containing proteins will likely be identified that interact with the LRAD3 cytoplasmic domain.

    “While the results obtained in the present study reveal that Fe65 does not interact with LRAD3, it is likely that other WW-domain containing proteins will be identified that do interact with the LRAD3 cytoplasmic domain.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    γ-secretase is presenilin 1 or 2 along with several other proteins that form the enzyme complex.

    “while the γ-secretase has been identified as presenillin 1 or 2 (De Strooper et al., 1999) along with several other proteins that form the enzyme complex (De Strooper, 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites De Strooper et al., 1999 source
    • cites De Strooper, 2003 source

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

    Interpretationreasoning

    Ligand binding may trigger signaling events.

    “Given the structure of the LRAD3 cytoplasmic domain, it also seems likely that ligand binding may trigger signaling events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    LRAD3 expression alters APP processing, lowering sAPPα and increasing Aβ secretion.

    “We further demonstrate that LRAD3 expression alters APP processing, such that lowered levels of sAPPα and increased amounts of the Aβ peptide are secreted into the media when LRAD3 is expressed.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    APP undergoes regulated intramembrane proteolysis.

    “The cellular trafficking of APP is complex, as APP undergoes regulated intramembrane proteolysis (Brown et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brown et al., 2000 source

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

    Premisecitation

    Proteolysis by β- and γ-secretase is thought to occur within endosomal compartments.

    “Proteolysis by the β- and γ-secretase is thought to occur within the endosomal compartments (Sisodia and Price, 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sisodia and Price, 1995 source

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

    Premisecitation

    β-secretase is a transmembrane aspartyl-proteinase termed BACE.

    “The β-secretase has been identified as a transmembrane aspartyl-proteinase termed BACE (Vassar et al., 1999)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vassar et al., 1999 source

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

    Interpretationcitation

    The PPPPY sequence in LRAD3 may also be recognized by molecules containing SH3 domains.

    “Interestingly, not only does the PPPPY sequence in LRAD3 conform to the WW domain binding consensus, but this region may also be recognized by molecules containing src homology 3 (SH3) domains (Pawson and Scott, 1997; Pawson, 1995; Cohen et al., 1995).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Pawson and Scott, 1997 source
    • cites Pawson, 1995 source
    • cites Cohen et al., 1995 source

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

    Premisecitation

    Presenilin-mediated cleavage of APP releases APP intracellular domain (ICD), which is thought to participate in signaling pathways via association with Fe65 and Tip60.

    “The presenilin-mediated cleavage of APP occurs within the transmembrane domain and releases the APP intracellular domain (ICD), which is thought to participate in signaling pathways via association with the adaptor protein Fe65 and the histone acetyltransferase Tip60 (Cao and Sudhof, 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cao and Sudhof, 2001 source

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

    Premisecitation

    Fe65 contains a WW domain, is expressed in the brain, associates with APP via a PTB domain and modulates its signaling properties.

    “Fe65, which contains a WW domain, is expressed in the brain and associates with APP via a PTB domain and modulates it’s signaling properties (Cao and Sudhof, 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cao and Sudhof, 2001 source
40 of 40

  • The paper relies on this without support.

    The HT22 cell line is a valid model of hippocampal neurons for studying LRAD3 and APP processing.

    “We found that the widely used mouse hippocampal neuronal cell line HT22 expresses LRAD3.”

  • The paper relies on this without support.

    The hippocampus CA1 region is relevant to Alzheimer's disease.

    “Since LRAD3 is prominently expressed in neurons of the hippocampus CA1 layer, a region of the brain that is relevant to Alzheimer’s disease, we initiated studies to determine if LRAD3 can influence the cellular processing of APP, a protein genetically implicated in the development of Alzheimer’s disease.”

  • The paper relies on this without support.

    The Aβ peptide is a major component of plaques in Alzheimer's patients.

    “a transmembrane protein that is proteolytically processed to generate the Aβ-peptide which is a major component of plaques in Alzheimer’s patients.”

  • The paper relies on this without support.

    The LDLa repeats of LRP, megalin, and the LDL receptor are responsible for binding ligands.

    “The LDLa repeats of LRP, megalin, and the LDL receptor are responsible for binding ligands.”

  • The paper relies on this without support.

    The polyproline sequence in LRAD3 is not the optimal motif for the Fe65 WW domain.

    “Although the polyproline sequence in LRAD3 is not the optimal motif for the Fe65 WW domain, given the importance of Fe65 in APP biology, we performed a co-immunoprecipitation experiment to determine if Fe65 is capable of associating with LRAD3.”
5 of 5

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Related

Authors
Ranganathan, S., Noyes, N. C., Migliorini, M., Winkles, J. A., Battey, F. D., Hyman, B. T., Smith, E., Yepes, M., Mikhailenko, I., & Strickland, D. K.
Affiliations
  • University of Maryland, Baltimore (US)
  • Harvard University (US)
  • Emory University (US)
ORCID
Venue
Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2011-07-27
Volume
31
Issue
30
Pages
10836-10846
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.5065-10.2011
PMC
PMC3189500
OpenAlex
W2014288364
Semantic Scholar
414b99b0b44382fbd2cdda902c1d4b27db4f1a94
Cited by
49
References
60
Citations by year
2026: 1 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 4
FWCI
2.31
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (PO1 HL54710, HL54710, 5t32hl007698-30)
  • National Heart, Lung, and Blood Institute (HL50784, T32 HL-007698, P01 HL54710, R01 HL050784, P01 HL054710)
  • National Institute of Neurological Disorders and Stroke (R01NS049478, NS 49478, R01 NS055126)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
amyloid precursor protein, APP trafficking, APP processing, amyloid-beta production, sAPPα, C99, beta-secretase, alpha-secretase, polyproline motif, hippocampus, Alzheimer's disease
MeSH terms
Animals, Cells, Cultured, Chlorocebus aethiops, Cerebral Cortex, Embryo, Mammalian, Endocytosis, Enzyme-Linked Immunosorbent Assay, Cricetinae, Humans, Molecular Weight, Neurons, Protein Binding, Receptors, LDL, RNA, Messenger, Transfection, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Sequence Analysis, Protein, Protein Transport, Immunoprecipitation, Mice

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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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