The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index; 23 of the 53 sources its claims cite were checked for support.
The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate
Open accessAbstract
BACE is a transmembrane protease with beta-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for gamma-secretase, leading to release of amyloid-beta peptide (Abeta), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
BACE1 interacts with the intracellular domain of LRP at the cell surface in lipid rafts, and this interaction leads to BACE-mediated cleavage of LRP. The authors conclude that LRP is a novel BACE1 substrate, processed in a manner analogous to APP.
Key findings
- LRP and BACE co-immunoprecipitate: endogenous LRP light chain (~85 kDa) was pulled down with anti-BACE from human brain, and BACE bands (~60 and 75 kDa) were detected in mLRP1 immunoprecipitates from transfected H4 cells.
- FLIM/FRET showed close proximity: BACE-V5 FITC lifetime was 2334 ± 72 ps alone vs. 2153 ± 55 ps with mLRP1-Myc-Cy3 (p < 0.0001); mLRP1-GFP was 2164 ± 10 ps alone vs. 1165 ± 8 ps with BACE-V5-Cy3 (p < 0.0001); endogenous N2a BACE-CT Alexa 488 was 1868 ± 116 ps alone vs. 1492 ± 293 ps with 11H4-Cy3 (p < 0.0001).
- The interaction was weakened by cholesterol depletion (Myc-LC FITC + BACE-NT Cy3: 2023 ± 173 ps vs. 2203 ± 83 ps after depletion, p < 0.001), and an LC-LDLR chimera lacking the LRP intracellular domain did not FRET with BACE.
- BACE activity increased LRP ectodomain shedding and LRP C-terminal fragment/intracellular domain release: WT-BACE increased SEAP-LRP shedding, catalytically inactive BACE D93/289A had no effect, BACE inhibitor and BACE siRNA reduced cleavage, and BACE co-transfection increased a 25-kDa LRP-CTF and LRP-Gal4/VP16 luciferase activity.
Methods
- Cell systems included H4, mouse neuroblastoma N2a, pac1, LRP-deficient CHO 13-5-1, HEK293, and primary cortical neurons from embryonic day 16 CD1 mice; constructs included Myc-LC, mLRP1-Myc, mLRP1-GFP, LRP165-Myc, LC-LDLR, SEAP-LRP, LRP-Gal4-VP16, BACE-V5/Myc/GFP, and BACE mutants.
- Protein interaction and localization were assessed by co-immunoprecipitation, immunocytochemistry/confocal microscopy, caveolae/noncaveolae fractionation, cholesterol depletion, human temporal cortex staining, and FLIM-based FRET.
- Functional processing was assayed by BACE internalization assays in LRP-null cells, SEAP-LRP ectodomain secretion, Western blotting for LRP-CTF with DAPT, and luciferase reporter assay for LRP-ICD release; statistics used Student’s t test.
Limitations
- Stated: whether LRP processing produces a stable LRP equivalent of Aβ is unknown; whether LRP-ICD has a transcriptional role under physiological conditions remains unknown; further studies are needed to determine if APP and LRP act co-operatively or competitively for secretase access and how LRP ligands affect these processes.
- Stated: Fe65 and mDab1 did not appear to mediate the BACE-LRP interaction under the conditions used, though multiple other adaptor proteins might mediate or impact it.
- Evident from the text: many interaction, shedding, CTF, and ICD experiments rely on transfected constructs and overexpression in cell lines; endogenous validation is limited to co-immunoprecipitation and FLIM in N2a cells, primary neurons, and human brain, with no in vivo causal test of LRP cleavage or downstream signaling.
Model-written summary. Check it against the paper before relying on it.
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Verification
Claims the paper makes
23 of 53 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
LRP potentially acts as a scaffolding complex in rafts for APP and for BACE.
“Thus, LRP, which is highly enriched in rafts, potentially acts as a scaffolding complex in rafts for APP and for BACE; such an interaction may help explain the observations that directing APP to rafts enhances -cleavage and A generation (13).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Ehehalt, 2003, J. Cell Biol. source
- Rests on an assumption: LRP is highly enriched in lipid rafts.
- Findingown data
BACE immunoprecipitated from co-transfected H4 cells pulls down mLRP1-Myc, with immunoreactive bands of approximately 100 kDa and 140 kDa.
“Immunoreactive bands of ϳ100 kDa (resembling mature furin-cleaved mLRP1-Myc) and ϳ140 kDa (resembling unprocessed Golgi and ER forms of mLRP1-Myc) (29) were detected in the immunoprecipitated sample and the whole cell lysate (Fig. 3A, lane 4).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [29] Mikhailenko, 2001, J. Biol. Chem. source
The passage headed “High Affinity α2M* Binding to LRP Requires Ligand Binding Repeats in Both Cluster I and Cluster II” (page unavailable) reports that Myc-tagged mini-receptors, including mLRP1, were processed by furin. It does not identify approximately 100-kDa and 140-kDa bands as mature and unprocessed mLRP1-Myc forms. The BACE immunoprecipitation is presented as the citing paper’s own result, not as a result attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingown data
Co-transfection with LC does not enhance BACE internalization from the cell surface in LRP-null CHO cells (13-5-1).
“Co-transfection with LC did not enhance BACE internalization from the cell surface in LRP-null CHO cells (13-5-1) in contrast to known enhancement of APP endocytosis with LC (20).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Pietrzik, 2002, EMBO J. source
- Interpretationcitation
The cleavage of LRP observed could modulate signaling roles of LRP in neurons.
“However, both LRP (48,49) and other members of the LDL receptor-related family (50) have been implicated as having signaling roles in neurons, and it seems likely that the cleavage of LRP we observe could modulate such signaling.”
Quote in the paperNot a substantial claim2 of 3 sources checked - Findingown data
Co-transfection with BACE substantially increases luciferase activity in the LRP-Gal4/VP16 assay.
“Co-transfection with BACE led to a substantial increase in luciferase activity suggesting that LRP undergoes BACE cleavage, leading ultimately to release of the cytoplasmic domain and translocation to the nucleus (Fig. 9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] May, 2002, J. Biol. Chem. source
The Results describe an LRP-Gal4/VP16 luciferase assay, but do not report BACE co-transfection. A search for BACE found only a Discussion passage about β-secretase cleavage of APP, not an effect of BACE on LRP reporter activity. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingown data
Co-transfecting LC with BACE increases LRP-CTF detected as a 25-kDa band.
“This led to an increase of LRP-CTF detected by Western blot as a 25-kDa band.”
Quote in the paperSubstantial claim- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Findingown data
The BACE-LRP interaction leads to release of secreted LRP in the media.
“Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane.”
Quote in the paperSubstantial claim - Findingown data
Repeating the experiment in the presence of DAPT detects an increased amount of the 25-kDa product.
“To confirm that this band is the substrate of ␥-secretase activity, we repeated this experiment in the presence of the ␥-secretase inhibitor DAPT, and detected an increased amount of the 25-kDa product.”
Quote in the paperSubstantial claim- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Findingown data
In human brain sections, including the hippocampal formation, similar co-localization results were observed in neurons expressing endogenous levels of LRP and BACE.
“By staining human brain sections, includ-ing the hippocampal formation, we were able to observe similar results in neurons expressing endogenous levels of LRP and BACE (Fig. 3D).”
Quote in the paperSubstantial claim - Findingown data
Catalytically inactive BACE D93/289A exhibits no effect on LRP ectodomain shedding.
“WT-BACE led to a significant increase in LRP ectodomain shedding compared with baseline, whereas, as expected, catalytically inactive BACE D93/289A exhibited no effect (Fig. 7A).”
Quote in the paperSubstantial claim- Rests on an assumption: BACE D93/289A is catalytically inactive.
- Findingown data
BACE induces subsequent release of the LRP intracellular domain from the membrane.
“Instead BACE induces LRP extracellular domain cleavage and subsequent release of the LRP intracellular domain from the membrane.”
Quote in the paperSubstantial claim - Findingown data
mLRP1 and BACE co-localized in the endosomal compartments stained by EEA1.
“mLRP1 and BACE co-localized in the endosomal compartments stained by EEA1 (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
mLRP1-positive structures largely overlapped with BACE-positive structures when they were co-expressed.
“mLRP1-positive structures largely overlapped with BACE-positive structures when they were co-expressed.”
Quote in the paperSubstantial claim - Findingown data
WT-BACE significantly increases LRP ectodomain shedding compared with baseline.
“WT-BACE led to a significant increase in LRP ectodomain shedding compared with baseline, whereas, as expected, catalytically inactive BACE D93/289A exhibited no effect (Fig. 7A).”
Quote in the paperSubstantial claim - Findingown data
BACE and LRP exhibit FRET specifically in punctate structures at the cell surface.
“additional experiments in which only cell surface Myc-LC (N-terminal Myc) and BACE-NT are immunostained demonstrate FRET (Table II) between BACE and LRP specifically in punctuate structures at the cell surface (Fig. 5B).”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Findingown data
The BACE-LRP interaction leads to subsequent release of the LRP intracellular domain from the membrane.
“Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane.”
Quote in the paperSubstantial claim - Findingown data
Equivalent FLIM results were obtained when BACE was tagged with GFP and when the acceptor and donor fluorophores were exchanged.
“Equivalent results were obtained when BACE was tagged with GFP and when the acceptor and donor fluorophores were exchanged (Table I).”
Quote in the paperNot a substantial claim - Findingown data
LRP was present in caveolae as well as in noncaveolae fractions.
“LRP was present in caveolae as well as in noncaveolae fractions (Fig. 2D), which is in accordance with our confocal data showing partial overlap with the lipid raft marker CTx-B.”
Quote in the paperNot a substantial claim - Findingown data
Cholesterol depletion weakens the interaction of BACE and LRP at the cell surface.
“Cholesterol depletion weakened the interaction of BACE and LRP at the cell surface (Fig. 5C).”
Quote in the paperSubstantial claim- Rests on an assumption: Cholesterol depletion with lovastatin/mevalonate and MβCD disrupts lipid rafts.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Findingown data
Endogenous LRP and BACE co-immunoprecipitate from human brain tissue.
“Thus, endogenous LRP and BACE co-immunoprecipitate.”
- Also stated in: § Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells. · plain
“A strong immunoreactive band of ϳ85 kDa (the expected size of the mature endogenous light chain of LRP, i.e. furin-cleaved form) (29) was detected in the sample lane (Fig. 3C, lane 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Mikhailenko, 2001, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- Also stated in: § Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells. · plain
- Findingown data
Our data demonstrate a close interaction of LRP and BACE in specific subcellular compartments.
“In summary, our data demonstrate a close interaction of LRP and BACE in specific subcellular compartments.”
Quote in the paperSubstantial claim - Findingown data
The BACE-LRP interaction leads to an increase in LRP C-terminal fragment.
“Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane.”
Quote in the paperSubstantial claim - Findingown data
Endogenous LRP and endogenous BACE closely interact at the cell surface in a neuronal cell type.
“This result demonstrates close protein-protein interaction between endogenous LRP and endogenous BACE at the cell surface in a neuronal cell type, paralleling the co-immunoprecipitation results.”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Findingown data
BACE induces LRP extracellular domain cleavage.
“Instead BACE induces LRP extracellular domain cleavage and subsequent release of the LRP intracellular domain from the membrane.”
Quote in the paperSubstantial claim - Findingown data
To a lesser extent, the Golgi marker GM130 also overlapped with mLRP1 and BACE.
“To a lesser extent, the Golgi marker GM130 also overlapped with mLRP1 and BACE (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data
On the cell surface, Myc-LC and BACE are partly co-localized with one another in lipid rafts.
“On the cell surface Myc-LC and BACE are partly co-localized with one another in lipid rafts.”
Quote in the paperNot a substantial claim - Findingown data
When expressed individually, both mLRP1 and BACE were localized mainly in punctate structures in the cells.
“When expressed individually, both mLRP1 and BACE were localized mainly in punctate structures in the cells.”
Quote in the paperNot a substantial claim - Findingown data
The LC-LDLR chimera, lacking the LRP intracellular domain, does not FRET with BACE.
“This construct did not FRET with BACE (Table II), further supporting the importance of the intracellular domain of LRP for this interaction.”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Findingown data
BACE overexpression leads to an increase of γ-secretase-like cleavage to release LRP-ICD.
“Moreover BACE overexpression leads to an increase of ␥-secretase-like cleavage to release LRP-ICD.”
Quote in the paperSubstantial claim - Findingown data
The BACE-LRP interaction does not appear to enhance BACE endocytosis from the cell surface.
“Surprisingly, the BACE-LRP interaction does not appear to enhance BACE endocytosis from the cell surface.”
Quote in the paperSubstantial claim - Findingown data
DAPT treatment for 12 h increases the LRP-CTF 25-kDa band.
“After treatment with DAPT for 12 h we observed an increase of the LRP-CTF 25-kDa band consistent with the observations of (28) suggesting ␥-cleavage of LRP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] May, 2002, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Findingown data
The light chain of LRP interacts with BACE on the cell surface in association with lipid rafts.
“Using a new fluorescence resonance energy transfer (FRET)based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts.”
- Also stated in: § Abstract · hedged
“we demonstrate that the LRP-ICD interacts with BACE and that this interaction seems to take place in lipid rafts on the cell surface.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Findingown data
Knocking down overexpressed BACE by BACE1-specific siRNA reduces processing of LRP by BACE.
“Knocking down overexpressed BACE by co-transfection of BACE1-specific siRNA reduced processing of LRP by BACE (Fig. 7C).”
Quote in the paperSubstantial claim- Rests on an assumption: BACE1-specific siRNA specifically knocks down BACE.
- Findingown data
No changes in FRET measures are observed with S498D, S498A, and L499A/L500A mutants of BACE.
“No changes in FRET measures were observed with these manipulations (data not shown).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Findingown data
BACE-mediated cleavage of the LRP extracellular domain leads to secretion of the shed domain into the extracellular milieu.
“Moreover, our SEAP-LC assay demonstrates that BACE-mediated cleavage of the LRP extracellular domain leads to secretion of the shed domain into the extracellular milieu.”
Quote in the paperSubstantial claim - Interpretationown data
LC and BACE are co-localized in distinct compartments of the cell including lipid rafts, Golgi and prominently in the endosomal compartment.
“The results of the immunocytochemistry suggest that LC and BACE are co-localized in distinct compartments of the cell including lipid rafts (Fig. 2C), Golgi and prominently in the endosomal compartment.”
Quote in the paperSubstantial claim - Interpretationown data
BACE and LRP interact on the cell surface distinctively in lipid rafts.
“This result strongly suggests that BACE and LRP interact on the cell surface distinctively in lipid rafts.”
Quote in the paperSubstantial claim- Rests on an assumption: Cholesterol depletion with lovastatin/mevalonate and MβCD disrupts lipid rafts.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Interpretationown data
LRP is a novel BACE substrate.
“Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.”
Quote in the paperSubstantial claim- Rests on an assumption: BACE directly cleaves LRP.
- Premisenone given
The LRP ligand binding domains interact with KPI-containing forms of APP.
“The LRP ligand binding domains interact with KPIcontaining forms of APP.”
Quote in the paperNot a substantial claim - Interpretationcitation
LRP undergoes γ-cleavage.
“suggesting ␥-cleavage of LRP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] May, 2002, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Interpretationown data
The intracellular or transmembrane domain of LRP is the site of interaction with BACE.
“This result implicates the intracellular or the transmembrane domain of LRP as the site of interaction.”
Quote in the paperSubstantial claim - Study design and conductown data
This experiment demonstrates the specificity of the proximity assay in this FLIM-based method of measuring FRET.
“This experiment demonstrates the specificity of the proximity assay in this FLIM-based method of measuring FRET.”
Quote in the paperSubstantial claim - Interpretationreasoning
Because LRP and BACE co-localize in lipid rafts at the cell surface, the interaction detected by FLIM also is lipid raft-associated.
“Because LRP and BACE co-localize in lipid rafts at the cell surface, we suggest that the interaction detected by FLIM also is lipid raft-associated.”
Quote in the paperNot a substantial claim - Interpretationown data
LRP does not appear to be critical for BACE recycling from the cell surface to endosomes.
“Thus, although LRP co-traffics with BACE to the cell surface, it does not appear to be critical for BACE recycling from the cell surface to endosomes.”
Quote in the paperSubstantial claim - Study design and conductown data
Negative control donor lifetimes in the absence of acceptor showed lifetimes equivalent to GFP, Alexa 488-IgG, or FITC IgG alone, in solution or with co-transfection with an empty vector.
“As a negative control, GFP, Alexa 488, or FITC lifetimes were measured in the absence of acceptor (Cy3), which showed lifetimes equivalent to GFP, Alexa 488-IgG, or FITC IgG alone, in solution or with co-transfection with an empty vector (pEGFP) measured in the presence of Cy3-labeled BACE-V5 or LC-Myc.”
Quote in the paperSubstantial claim - Interpretationreasoning
LRP has a complex role in modulating APP processing.
“Our current data, showing an interaction between LRP and BACE, when viewed in the context of previous studies of APP-LRP interactions, suggest that LRP has a complex role in modulating APP processing.”
Quote in the paperSubstantial claim - Interpretationown data
LRP is processed by BACE in a fashion analogous to APP processing.
“Taken together, these data suggest a close interaction between BACE and LRP on the cell surface and suggest that LRP is processed by BACE in a fashion analogous to APP processing.”
Quote in the paperSubstantial claim - Interpretationown data
The major interaction site is the intracellular domain of LRP.
“Because even the LRP165 construct (which lacks ligand binding domains and most of the extracellular part of LRP) interacts with the BACE intracellular domain and the LC-LDLR-chimera lacking the LRP intracellular domain did not interact with BACE, we postulate that the major interaction site is the intracellular domain of LRP.”
Quote in the paperSubstantial claim - Interpretationown data
The intracellular domain of LRP is important for the LRP-BACE interaction.
“further supporting the importance of the intracellular domain of LRP for this interaction.”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Interpretationown data
BACE interacts with the intracellular domain of LRP.
“In the present study, we have demonstrated that BACE interacts with the intracellular domain of LRP, a multifunctional endocytic receptor.”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Interpretationown data
BACE-mediated cleavage of LRP generates a CTF for γ-cleavage.
“These results are consistent with a BACE-mediated cleavage of LRP, generating a CTF for ␥-cleavage.”
Quote in the paperSubstantial claim- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Interpretationown data
BACE internalization is not mediated by LRP under these conditions.
“Thus it appears that BACE internalization is not mediated by LRP under these conditions.”
Quote in the paperSubstantial claim - Interpretationown data
LRP and BACE interact at the cell surface in raft compartments.
“Taken together with the co-immunoprecipitation data, our results strongly support the conclusion that LRP and BACE interact at the cell surface in raft compartments.”
Quote in the paperSubstantial claim- Rests on an assumption: Cholesterol depletion with lovastatin/mevalonate and MβCD disrupts lipid rafts.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
- Interpretationown data
There is a close interaction between BACE and LRP on the cell surface.
“Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.”
- Also stated in: § Abstract · hedged
“Taken together, these data suggest a close interaction between BACE and LRP on the cell surface and suggest that LRP is processed by BACE in a fashion analogous to APP processing.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Probably not a substantial claim. 26
- It may state two separate claims as one. 29
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMultiple intracellular adaptor and scaffolding proteins bind the LRP 100 amino acid cytoplasmic tail.
“Multiple intracellular adaptor and scaffolding proteins bind the LRP 100 amino acid cytoplasmic tail (16,17);”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [16] Herz, 2001, J. Clin. Investig. source
The sections “Interactions with intracellular adapter and scaffold proteins” and “Structural organization of LRP” state that multiple cytoplasmic adaptor and scaffold proteins interact with the LRP tail. Our copy does not specify that the tail is 100 amino acids long, so that numerical detail is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [17] Li, 2001, Mol. Neurobiol. source
It may state two separate claims as one.
Premisecitationγ-Secretase cleavage of LRP leads to release of the LRP intracellular domain (LRP-ICD), which can translocate to the nucleus and interact with Tip60.
“Furthermore, and as with APP, ␥-secretase cleavage of LRP leads to release of the LRP intracellular domain (LRP-ICD), which can translocate to the nucleus and interact with Tip60 (27,28).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [27] Kinoshita, 2003, J. Biol. Chem. source
The Discussion says LRP cleavage releases its intracellular domain, which translocates to the nucleus; Fig. 5 reports close interaction with Tip60 there. The Discussion describes γ-secretase as the probable cause of cleavage, so the citing sentence states that mechanism more definitively than the source does. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [28] May, 2002, J. Biol. Chem. source
The Abstract reports release of the LRP intracellular domain by a γ-secretase-like activity, and the paper says FE65 can promote its nuclear translocation under certain conditions. It does not establish an LRP-ICD interaction with Tip60: a later passage (indexed as Abstract; page unavailable) raises the possibility that FE65 binding to LRP and recruitment of Tip60 are mutually exclusive, and its reporter assay did not show Tip60-dependent activity. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationProteolysis of LRP by matrix metalloproteases was recently reported.
“proteolysis of LRP by matrix metalloproteases was recently reported (25);”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Rozanov, 2004, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAn interaction between the C-terminal domain of APP and LRP, mediated by the cytoplasmic adaptor protein Fe65, impacts APP internalization.
“In addition, an interaction between the C-terminal domain of APP and LRP, mediated by the cytoplasmic adaptor protein Fe65, impacts APP internalization (18 -23).”
Quote in the paperNot a substantial claim3 of 6 sources checked- cites [18] Kounnas, 1995, Cell source
- cites [19] Ulery, 2000, J. Biol. Chem. source
The discussion (page unavailable in our copy) says Fe65 binds the cytoplasmic portions of APP and LRP and may link them. It also proposes that APP–LRP interaction modulates APP trafficking through the endocytic pathway. It does not establish that Fe65 mediates an interaction that impacts APP internalization; that mechanism remains a possibility rather than a demonstrated finding. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [20] Pietrzik, 2002, EMBO J. source
In “Abnormalities in APP processing are isoform independent” (page not given), the paper reports reduced APP internalization without LRP and its restoration by an LRP C-terminal construct. The Discussion (page not given) proposes an adaptor linking APP and LRP but says whether adaptors coordinate their internalization awaits further study. It mentions Fe65 in connection with transcription, not as an established mediator of APP internalization. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [21] Rebeck, 2001, Brain Res. Mol. Brain Res. source
- cites [22] Kinoshita, 2001, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [23] Trommsdorff, 1998, J. Biol. Chem. source
The Results show that distinct FE65 domains bind the cytoplasmic tails of LRP and APP, and the Discussion says FE65 could in principle link them. The paper proposes that this might affect APP trafficking or receptor endocytosis, but does not demonstrate an effect on APP internalization; its conclusion says that physiological relevance for endocytosis remains to be tested. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA family of GGA adaptor proteins and PLSCR1 directly interact with the BACE tail.
“A family of GGA adaptor proteins and the phospholipid scramblase 1 (PLSCR1) have been shown to directly interact with the BACE tail (42,45).”
Quote in the paperNot a substantial claim2 of 2 sources checkedIt may state two separate claims as one.
Interpretationown dataLRP undergoes BACE cleavage, leading ultimately to release of the cytoplasmic domain and translocation to the nucleus.
“Co-transfection with BACE led to a substantial increase in luciferase activity suggesting that LRP undergoes BACE cleavage, leading ultimately to release of the cytoplasmic domain and translocation to the nucleus (Fig. 9).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] May, 2002, J. Biol. Chem. source
The paper reports release of LRP’s cytoplasmic domain and, in the Abstract, says FE65 can stimulate its translocation into the nucleus under certain conditions. It does not establish BACE cleavage as the initiating step; the Discussion instead identifies furin and metalloproteinase cleavage and implicates a γ-secretase-like activity in tail release. The citing sentence’s BACE co-transfection result is its own finding, not a result attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBesides APP, identified BACE substrates include APLP1 and -2, PSGL-1, and a membrane-bound sialyltransferase.
“Besides APP, the few BACE substrates that have been identi-fied include the APP homologues APLP1 and -2 (5), P-selectin glycoprotein ligand-1 (PSGL-1), and a membrane-bound sialyltransferase (6).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationLRP-ICD translocates to the nucleus and interacts with Fe65 and Tip60.
“Although LRP-ICD has been shown to translocate to the nucleus and interact with Fe65 and Tip60 (28,47), whether or not it has a transcriptional role under physiological conditions remains unknown.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [28] May, 2002, J. Biol. Chem. source
The Abstract says that FE65 can stimulate translocation of the LRP tail fragment into the nucleus under certain conditions, and the Discussion says LRP binds FE65. But the Discussion (Fig. 6C) suggests that FE65 binding to the LRP tail and binding to Tip60 are mutually exclusive; it does not show LRP-ICD interacting with Tip60. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [47] Kinoshita, 2002, J. Biol. Chem. source
The Results and Discussion describe APP-CT, not LRP-ICD, translocating to the nucleus and interacting with Fe65 and Tip60; no page numbers are available in our copy. Searches for LRP-ICD, its expanded name, and LRP found no passage addressing whether LRP-ICD does so. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP and other LDL receptor-related family members have signaling roles in neurons.
“However, both LRP (48,49) and other members of the LDL receptor-related family (50) have been implicated as having signaling roles in neurons, and it seems likely that the cleavage of LRP we observe could modulate such signaling.”
Quote in the paperNot a substantial claim2 of 3 sources checkedProbably not a substantial claim.
PremisecitationLRP is a known γ-substrate.
“Because LRP is a known ␥-substrate, we hypothesized that it might also be cleaved by -secretase.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] May, 2002, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDirecting APP to rafts enhances β-cleavage and Aβ generation.
“such an interaction may help explain the observations that directing APP to rafts enhances -cleavage and A generation (13).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Ehehalt, 2003, J. Cell Biol. source
The Results section on antibody-induced cross-linking (page not provided) reports increased Aβ secretion when APP and BACE1 were copatched in rafts. The Discussion says this clustering can promote β-cleavage, but also states that partitioning APP and BACE1 into rafts alone is insufficient: cleavage normally depends on endocytosis. The claim omits that distinction and implies that directing APP to rafts by itself produces both effects. (LLM, conf=0.85)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataLRP deletion constructs LC and LRP165 both interact strongly with BACE.
“LC, which contains the -chain of LRP, and LRP165, a construct that contains only the 100 amino acid intracellular domain, the transmembrane domain and a very small extension beyond the membrane, both interacted strongly with BACE (Table I).”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
It may state two separate claims as one.
Findingown dataFITC bound to BACE-V5 in the absence of acceptor has a uniform lifetime and a single lifetime peak.
“FITC bound to BACE-V5 in the absence of acceptor has a uniform lifetime and a single lifetime peak (Fig. 4A);”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe presence of BACE further increases the 25-kDa band intensity, while catalytically inactive BACE mutant does not increase it.
“The presence of BACE further increased and co-transfection with catalytically inactive BACE mutant did not increase this band intensity (Fig. 8).”
Quote in the paperSubstantial claim- Rests on an assumption: BACE D93/289A is catalytically inactive.
- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
It may state two separate claims as one.
Findingown datamLRP1 immunoprecipitates contain BACE, with doublet bands of approximately 60 and 75 kDa.
“The doublet bands of ϳ60 and 75 kDa were detected only in lane 1 and in the control lysate lane (Fig. 3B), suggesting that BACE is present in the mLRP1 immunoprecipitates.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBACE and LRP co-localize and are in close proximity in H4 and N2a cells, primarily in endosomes and at the cell surface.
“Co-localization and close proximity in both H4 and N2a cells was shown by confocal microscopy and FRET-based proximity assays, suggesting co-localization primarily in endosomes and at the cell surface.”
Quote in the paperSubstantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
It may state two separate claims as one.
Findingown dataIn the control with mLRP1-GFP and Myc-BACE, although there was striking co-localization, no lifetime change was observed.
“Although there was striking co-localization, no lifetime change was observed.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the presence of mLRP1-Cy3 acceptor, FITC has two distinct lifetimes and is faster, representing FRETting molecules.
“in the presence of mLRP1-Cy3 acceptor, FITC has two distinct lifetimes and is faster, representing “FRETting” molecules (Fig. 4B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the absence of an acceptor fluorophore, the lifetime of FITC conjugated to IgG is approximately 2300 ps, GFP approximately 2200 ps, and Alexa 488 approximately 1900 ps.
“In the absence of an acceptor fluorophore, the lifetime of FITC conjugated to IgG (hereafter referred to simply as FITC) is ϳ2300 ps, GFP ϳ2200 ps, and Alexa 488 is ϳ1900 ps.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNo FRET is detected between BACE and Fe65 or between BACE and mDab1 under the conditions utilized.
“However, under the conditions utilized we did not detect any FRET between BACE and Fe65 or between BACE and mDab1 (data not shown).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
It may state two separate claims as one.
Findingown dataBACE and LRP co-immunoprecipitate from overexpressing cells and from endogenous BACE and LRP in human brain samples and primary neurons.
“The interaction was demonstrated by co-immunoprecipitation of BACE and LRP from overexpressing cells and from endogenous BACE and LRP in human brain samples and primary neurons.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe lifetime of FITC attached to the C terminus of BACE-V5 alone (2334 ± 72 ps) was significantly shortened when co-expressed mLRP1-Myc was C-terminally labeled by Cy3 (2153 ± 55 ps, p < 0.0001), indicating FRET between the two fluorophores.
“The lifetime of FITC attached to the C terminus of BACE-V5 alone (2334 Ϯ 72 ps) was significantly shortened when co-expressed mLRP1-Myc was C-terminally labeled by Cy3 (2153 Ϯ 55 ps, p Ͻ 0.0001), indicating FRET between the two fluorophores (Table I).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBACE activity at endogenous levels leads to an increase of secreted LRP in the medium as well as LRP-CTF.
“We found that BACE activity at endogenous levels leads to an increase of secreted LRP in the medium as well as LRP-CTF, analogous to APP processing.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenLRP is a type I integral membrane protein with a 515-kDa extracellular α-chain non-covalently bound to the 85 kDa membrane-spanning β-chain.
“The low density lipoprotein receptor-related protein, LRP, is a type I integral membrane protein with a 515-kDa extracellular ␣-chain non-convalently bound to the 85 kDa membranespanning -chain.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataNo bleedthrough or mis-excitation of Cy3 was observed under the FLIM conditions used.
“No bleedthrough or mis-excitation of Cy3 was observed under these conditions.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBACE is a type I membrane-associated aspartyl protease that cleaves APP.
“BACE is a transmembrane protease with -secretase activity that cleaves the amyloid precursor protein (APP).”
- Also stated in: § Abstract · plain
“BACE 1 ( site of APP-cleaving enzyme) is a type I membrane-associated aspartyl protease that cleaves APP (1)(2)(3)(4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (1)(2)(3)(4)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Also stated in: § Abstract · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataSpecific knockdown of more than 70% of overexpressing BACE was observed starting 24 h after transfection by Western blot and immunostaining.
“Specific knockdown of Ͼ70% of overexpressing BACE was observed starting 24 h after transfection by Western blot and immunostaining (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBACE has so far appeared to be relatively specific.
“In contrast to ␥-secretase, where at least 15 substrates have been described (44), BACE has so far appeared to be relatively specific.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] De Strooper, 2003, Neuron source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMeasurable amounts of APP and BACE are present on the plasma membrane and in lipid rafts.
“Measurable amounts of APP and BACE are present on the plasma membrane (10 -12) and in lipid rafts (12)(13)(14).”
Quote in the paperNot a substantial claim0 of 4 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP's four extracellular binding domains mediate endocytosis of a wide array of ligands, including APP, apolipoprotein E and α2-macroglobulin.
“its four extracellular binding domains mediate endocytosis of a wide array of ligands, including several of potential importance for Alzheimer disease pathophysiology: APP, apolipoprotein E and ␣ 2 -macroglobulin (16 -18).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMT1-MMP also cleaves APP.
“MT1-MMP also cleaves APP (26)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Higashi, 2003, Biochemistry source
It may state two separate claims as one.
Interpretationown dataThe observed BACE effect on LRP cleavage has physiologic relevance and is not restricted to cells overexpressing BACE.
“indicating that the observed effect has physiologic relevance and is not restricted to cells overexpressing BACE (Fig. 7B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe 60-kDa band represents endogenous BACE, whereas the 75-kDa band represents transfected BACE containing a V5-His tag.
“The 60-kDa band represents endogenous BACE, whereas the 75-kDa band represents transfected BACE containing a V5-His tag.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPost-translational processing of BACE involves N-glycosylation, removal of its prodomain by a furin-like protease, and further complex glycosylation.
“Post-translational processing of BACE involves N-glycosylation, removal of its prodomain by a furin-like protease, and further complex glycosylation (7)(8)(9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (7)(8)(9)
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. It may state two separate claims as one.
Premisenone givenLRP is found on the cell surface and cycles between the cell membrane and endosomes.
“It is also found on the cell surface and cycles between the cell membrane and endosomes.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBACE and APP are internalized from the cell surface to early endosomes and cycle between the cell membrane and endosomes.
“BACE and APP are internalized from the cell surface to early endosomes and cycle between the cell membrane and endosomes (10,11,15).”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataExamination of the FLIM images suggests that LRP and BACE interact at the cell surface and in endosomal compartments.
“Examination of the FLIM images of transfected cells suggests that LRP and BACE interact (red pseudocolor) at the cell surface and in endosomal compartments.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEctodomain shedding of LRP has been described.
“Ectodomain shedding of LRP has been described (24)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Quinn, 1999, Exp. Cell Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAuthenticity of the PCR-generated constructs was confirmed by sequencing.
“Authenticity of the PCRgenerated constructs was confirmed by sequencing.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataLRP is a substrate for both BACE and γ-secretase.
“Thus we now show that LRP is a substrate for both BACE and ␥-secretase, identified as APP-processing enzymes.”
Quote in the paperSubstantial claim- Rests on an assumption: BACE D93/289A is catalytically inactive.
- Rests on an assumption: BACE1-specific siRNA specifically knocks down BACE.
- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAfter glycosylation, BACE co-traffics with APP and is rapidly transported to the Golgi apparatus and distal secretory pathway.
“After glycosylation, BACE co-traffics with APP and is rapidly transported to the Golgi apparatus and distal secretory pathway (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Creemers, 2001, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Study design and conductown dataControl precipitate from samples lacking anti-BACE antibody showed only a weak immunoreactive band, and samples lacking cell extract did not contain this band.
“Control precipitate from samples lacking anti-BACE Ab (lane 2) showed only a weak immunoreactive band, and samples lacking cell extract (lane 3) did not contain this band.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSialyltransferase and PSGL-1, in addition to APP and its homologues APLP1 and 2, are the only other reported substrates of BACE.
“Sialyltransferase and PSGL-1, in addition to APP and its homologues APLP1 and 2 are the only other reported substrates of BACE (6,43).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationApoE, a LRP ligand, is co-localized with APP and BACE in lipid rafts.
“This is in good accordance with a recent article showing that ApoE, a LRP ligand, is co-localized with APP and BACE in lipid rafts (46).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Kawarabayashi, 2004, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe LRP C-terminal domain mediates an interaction with APP in similar cell compartments.
“The LRP C-terminal domain also mediates an interaction with APP in similar cell compartments (22).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Kinoshita, 2001, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Study design and conductown dataAnalogous results were obtained using three different fluorophores, multiple different antibody pairs, endogenous or transfected LRP and BACE, and two different cell types.
“Analogous results were obtained using three different fluorophores, multiple different antibody pairs, endogenous or transfected LRP and BACE, and two different cell types.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The mLRP1 and Myc-LC constructs are functionally similar to full-length LRP.
“These constructs were used instead of full-length LRP because of its functional similarity to and better expression than full-length LRP.”
The paper relies on this without support.
BACE directly cleaves LRP.
“LRP is a novel BACE substrate.”
“BACE induces LRP extracellular domain cleavage”
The paper relies on this without support.
Cholesterol depletion with lovastatin/mevalonate and MβCD disrupts lipid rafts.
“To test the hypothesis that this interaction occurs in rafts we cholesterol depleted the cells and repeated the cell surface FLIM experiment.”
“Cholesterol depletion was performed with lovastatin/mevalonate for 24 h and MCD for 10 min.”
The authors state this as an assumption.
FRET requires the two fluorophores to be within less than 10 nm of each other.
“The two fluoro-phores must be quite close (Ͻ10 nm) to support FRET; tagging LRP and BACE molecules “across the membrane” from one another or after cholesterol depletion abolishes FRET despite continued co-localization at the light level.”
The paper relies on this without support.
LRP is highly enriched in lipid rafts.
“Thus, LRP, which is highly enriched in rafts, potentially acts as a scaffolding complex in rafts for APP and for BACE; such an interaction may help explain the observations that directing APP to rafts enhances -cleavage and A generation (13).”
The paper relies on this without support.
BACE D93/289A is catalytically inactive.
“WT-BACE led to a significant increase in LRP ectodomain shedding compared with baseline, whereas, as expected, catalytically inactive BACE D93/289A exhibited no effect (Fig. 7A).”
The paper relies on this without support.
BACE1-specific siRNA specifically knocks down BACE.
“Knocking down overexpressed BACE by co-transfection of BACE1-specific siRNA reduced processing of LRP by BACE (Fig. 7C).”
The paper relies on this without support.
The 25-kDa band detected by Western blot is LRP-CTF.
“This led to an increase of LRP-CTF detected by Western blot as a 25-kDa band.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Whole-cell lysate assigned to conflicting lanes
MinorThe results text places the whole-cell lysate for Figure 3A in lane 4, but the Figure 3A caption identifies lane 5 as the positive-control lysate.
“were detected in the immunoprecipitated sample and the whole cell lysate (Fig. 3A, lane 4).”
“Anti-Myc recognizes precursor endoplasmic reticulum and Golgi forms (labeled p) as well as -chains of mature proteins (labeled b) (positive control, lane 5) (29).”
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The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis
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Metadata
- Authors
- von Arnim, C. A. F., Kinoshita, A., Peltan, I. D., Tangredi, M. M., Herl, L., Lee, B. M., Spoelgen, R., Hshieh, T. T., Ranganathan, S., Battey, F. D., Liu, C.-X., Bacskai, B. J., Sever, S., Irizarry, M. C., Strickland, D. K., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hyman, Bradley T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 280
- Issue
- 18
- Pages
- 17777-17785
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2137023074
- Cited by
- 258
- References
- 50
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 12 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 19 · 2012: 24
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Federation for Aging Research
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (AG15379)
- National Institute on Aging (P01AG015379, AG 12406, P50AG005134)
- National Heart, Lung, and Blood Institute (R01HL050784, P01HL054710)
- National Institute of Biomedical Imaging and Bioengineering (R01EB000768)
- 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
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- low density lipoprotein receptor-related protein, BACE1, beta-secretase, amyloid precursor protein, lipid rafts, Alzheimer's disease, amyloid-beta, endocytosis
- MeSH terms
- Animals, Cricetinae, Humans, Endopeptidases, Substrate Specificity, Aspartic Acid Endopeptidases, CHO Cells, Low Density Lipoprotein Receptor-Related Protein-1, Cell Line, Tumor, Mice, Amyloid Precursor Protein Secretases
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 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (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.
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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