The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index; 25 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
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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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Cites
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Verification
Claims the paper makes
25 of 53 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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 Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Supportedcites [13] Ehehalt, 2003, J. Cell Biol. source
The citation is attached to the observation about raft-directed APP processing, not to the citing authors’ proposed LRP scaffold. The Results report that copatching APP and BACE1 increased Aβ secretion, and the Discussion’s Figure 8 model links their raft clustering to β-cleavage. The paper does not establish the proposed role for LRP. (LLM, conf=0.88)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Rests on an assumption: LRP is highly enriched in lipid rafts.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
What the sources say
- Partly supportedcites [29] Mikhailenko, 2001, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Supportedcites [20] Pietrzik, 2002, EMBO J. source
The citation is attached to the contrast about APP endocytosis, not the citing authors’ BACE result. In “Abnormalities in APP processing are isoform independent” (Fig. 6A; page unavailable), the paper reports that introducing LRP-CT largely restored APP internalization in LRP-deficient fibroblasts. (LLM, conf=0.90)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Supportedcites [48] Bacskai, 2000, Proc. Natl. Acad. Sci. U. S. A. source
The Discussion reports that LRP serves as a neuronal signaling receptor: stimulation through LRP elicits a calcium response. The suggestion that the citing authors’ observed cleavage could modulate that signaling is their own inference, not a finding attributed to this source. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [49] Boucher, 2002, J. Biol. Chem. source
- Supportedcites [50] Trommsdorff, 1999, Cell source
The cited paper supports the statement attached to citation 50: its Abstract reports signaling functions for VLDLR and ApoER2, members of the LDL receptor family, in neuronal migration. Its Discussion likewise describes a role for the family in cellular signaling beyond ligand endocytosis. The suggestion that LRP cleavage could modulate signaling is the citing authors’ own inference, not a finding attributed to this source. (LLM, conf=0.93)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Could not verifycites [28] May, 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This led to an increase of LRP-CTF detected by Western blot as a 25-kDa band.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: BACE D93/289A is catalytically inactive.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Instead BACE induces LRP extracellular domain cleavage and subsequent release of the LRP intracellular domain from the membrane.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mLRP1 and BACE co-localized in the endosomal compartments stained by EEA1 (Fig. 2A).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mLRP1-positive structures largely overlapped with BACE-positive structures when they were co-expressed.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Equivalent results were obtained when BACE was tagged with GFP and when the acceptor and donor fluorophores were exchanged (Table I).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cholesterol depletion weakened the interaction of BACE and LRP at the cell surface (Fig. 5C).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
What the sources say
- Not checked yetcites [29] Mikhailenko, 2001, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, our data demonstrate a close interaction of LRP and BACE in specific subcellular compartments.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Instead BACE induces LRP extracellular domain cleavage and subsequent release of the LRP intracellular domain from the membrane.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To a lesser extent, the Golgi marker GM130 also overlapped with mLRP1 and BACE (Fig. 2B).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the cell surface Myc-LC and BACE are partly co-localized with one another in lipid rafts.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When expressed individually, both mLRP1 and BACE were localized mainly in punctate structures in the cells.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This construct did not FRET with BACE (Table II), further supporting the importance of the intracellular domain of LRP for this interaction.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover BACE overexpression leads to an increase of ␥-secretase-like cleavage to release LRP-ICD.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Surprisingly, the BACE-LRP interaction does not appear to enhance BACE endocytosis from the cell surface.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Not checked yetcites [28] May, 2002, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Not checked yet
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Knocking down overexpressed BACE by co-transfection of BACE1-specific siRNA reduced processing of LRP by BACE (Fig. 7C).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: BACE1-specific siRNA specifically knocks down BACE.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No changes in FRET measures were observed with these manipulations (data not shown).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This result strongly suggests that BACE and LRP interact on the cell surface distinctively in lipid rafts.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: BACE directly cleaves LRP.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The LRP ligand binding domains interact with KPIcontaining forms of APP.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“suggesting ␥-cleavage of LRP.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Not checked yetcites [28] May, 2002, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
- Not checked yet
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This result implicates the intracellular or the transmembrane domain of LRP as the site of interaction.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesWhat the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This experiment demonstrates the specificity of the proximity assay in this FLIM-based method of measuring FRET.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesWhat the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Generation of Expression Constructs of LRP and BACE and BACE
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“further supporting the importance of the intracellular domain of LRP for this interaction.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the present study, we have demonstrated that BACE interacts with the intracellular domain of LRP, a multifunctional endocytic receptor.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results are consistent with a BACE-mediated cleavage of LRP, generating a CTF for ␥-cleavage.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 25-kDa band detected by Western blot is LRP-CTF.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus it appears that BACE internalization is not mediated by LRP under these conditions.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · hedged
- Probably not a substantial claim. 26
- It may state two separate claims as one. 29
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Multiple intracellular adaptor and scaffolding proteins bind the LRP 100 amino acid cytoplasmic tail (16,17);”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Partly supportedcites [16] Herz, 2001, J. Clin. Investig. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [17] Li, 2001, Mol. Neurobiol. source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Partly supportedcites [27] Kinoshita, 2003, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [28] May, 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“proteolysis of LRP by matrix metalloproteases was recently reported (25);”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Supportedcites [25] Rozanov, 2004, J. Biol. Chem. source
The Results report that MT1-MMP proteolyzed LRP and that MT2-MMP, MT3-MMP, and MT4-MMP also degraded it in vitro. The Discussion likewise identifies these matrix metalloproteinases as capable of cleaving LRP. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked — no full text of the sourcecites [18] Kounnas, 1995, Cell source
- Partly supportedcites [19] Ulery, 2000, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [20] Pietrzik, 2002, EMBO J. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [21] Rebeck, 2001, Brain Res. Mol. Brain Res. source
- Not checked yetcites [22] Kinoshita, 2001, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
- Partly supportedcites [23] Trommsdorff, 1998, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Supportedcites [16] Herz, 2001, J. Clin. Investig. source
The Structural organization of LRP section describes four clusters of extracellular ligand-binding repeats and their role in ligand internalization. The Potential roles in Alzheimer disease section states that LRP serves as a receptor for APP, apoE, and α2-macroglobulin; Table 1 lists all three among ligands binding its extracellular domain. No page numbers are available in our copy. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [17] Li, 2001, Mol. Neurobiol. source
- Not checked — no full text of the sourcecites [18] Kounnas, 1995, Cell source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“BACE and APP are internalized from the cell surface to early endosomes and cycle between the cell membrane and endosomes (10,11,15).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked — no full text of the sourcecites [10] Kinoshita, 2003, J. Cell Sci. source
- Not checked — no full text of the sourcecites [11] Huse, 2000, J. Biol. Chem. source
- Partly supportedcites [15] Walter, 2001, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The introduction says BACE moves from the cell surface to early endosomes and can recycle to the surface; the trafficking results also show BACE entering early endosomes. The paper reports APP colocalization with BACE, but the passages do not establish that APP follows the same internalization and recycling route. (LLM, conf=0.87)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“A family of GGA adaptor proteins and the phospholipid scramblase 1 (PLSCR1) have been shown to directly interact with the BACE tail (42,45).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
What the sources say
- Supportedcites [42] He, 2002, FEBS Lett. source
The Introduction and Discussion report that the C-terminal region of memapsin 2 (BACE) binds the VHS domains of GGA1 and GGA2. This supports the GGA interaction attributed to this paper; the sentence has a second citation for the separate PLSCR1 claim. (LLM, conf=0.92)
- Supportedcites [45] Kametaka, 2003, J. Biol. Chem. source
The Results report that PLSCR1 interacts with the BACE tail in yeast two-hybrid and in vitro binding assays. The Discussion states that GGA adaptor proteins have also been shown to directly interact with the BACE tail. (LLM, conf=0.92)
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Partly supportedcites [28] May, 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Supportedcites [5] Li, 2004, J. Biol. Chem. source
The citation to this paper is attached specifically to APLP1 and APLP2, not to PSGL-1 or the sialyltransferase. The Discussion states that BACE 1 cleaves both APLP1 and APLP2 and summarizes the experimental evidence. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [6] Kitazume, 2001, Proc. Natl. Acad. Sci. U. S. A. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Partly supportedcites [28] May, 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
- Could not verifycites [47] Kinoshita, 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Supportedcites [48] Bacskai, 2000, Proc. Natl. Acad. Sci. U. S. A. source
The citation to this paper is attached to LRP’s signaling role, not the separate claim about other family members or the authors’ suggestion about cleavage. The paper’s Discussion reports that stimulation through LRP elicits a calcium response in neurons and concludes that LRP also serves as a signaling receptor. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [49] Boucher, 2002, J. Biol. Chem. source
- Supportedcites [50] Trommsdorff, 1999, Cell source
The Abstract identifies VLDLR and ApoER2 as LDL receptor family members with signaling functions in the Reelin pathway. The Discussion likewise describes their role in neuronal migration signaling. This supports the portion of the sentence attributed to citation 50; the separate claims about LRP and its cleavage are not attributed to this source. (LLM, conf=0.93)
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Because LRP is a known ␥-substrate, we hypothesized that it might also be cleaved by -secretase.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
What the sources say
- Supportedcites [28] May, 2002, J. Biol. Chem. source
The Abstract reports that LRP’s cytoplasmic domain is released by a γ-secretase-like activity. The Discussion reports that γ-secretase inhibitors strongly inhibited LRP tail cleavage, supporting the description of LRP as a γ-secretase substrate. (LLM, conf=0.90)
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“such an interaction may help explain the observations that directing APP to rafts enhances -cleavage and A generation (13).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Partly supportedcites [13] Ehehalt, 2003, J. Cell Biol. sourceExperimental — accuracy not yet measured
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)
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FITC bound to BACE-V5 in the absence of acceptor has a uniform lifetime and a single lifetime peak (Fig. 4A);”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The presence of BACE further increased and co-transfection with catalytically inactive BACE mutant did not increase this band intensity (Fig. 8).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although there was striking co-localization, no lifetime change was observed.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in the presence of mLRP1-Cy3 acceptor, FITC has two distinct lifetimes and is faster, representing “FRETting” molecules (Fig. 4B).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, under the conditions utilized we did not detect any FRET between BACE and Fe65 or between BACE and mDab1 (data not shown).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: FRET requires the two fluorophores to be within less than 10 nm of each other.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No bleedthrough or mis-excitation of Cy3 was observed under these conditions.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Generation of Expression Constructs of LRP and BACE and BACE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not matchedcites (1)(2)(3)(4)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Abstract · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Specific knockdown of Ͼ70% of overexpressing BACE was observed starting 24 h after transfection by Western blot and immunostaining (data not shown).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Generation of Expression Constructs of LRP and BACE and BACE
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In contrast to ␥-secretase, where at least 15 substrates have been described (44), BACE has so far appeared to be relatively specific.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [44] De Strooper, 2003, Neuron source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Measurable amounts of APP and BACE are present on the plasma membrane (10 -12) and in lipid rafts (12)(13)(14).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked — no full text of the sourcecites [10] Kinoshita, 2003, J. Cell Sci. source
- Not checked — no full text of the sourcecites [11] Huse, 2000, J. Biol. Chem. source
- Not checked — no full text of the sourcecites [12] Riddell, 2001, Curr. Biol. source
- Not matchedcites (12)(13)(14)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“MT1-MMP also cleaves APP (26)”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked — no full text of the sourcecites [26] Higashi, 2003, Biochemistry source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that the observed effect has physiologic relevance and is not restricted to cells overexpressing BACE (Fig. 7B).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > BACE Internalization Assay-Because
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The 60-kDa band represents endogenous BACE, whereas the 75-kDa band represents transfected BACE containing a V5-His tag.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Post-translational processing of BACE involves N-glycosylation, removal of its prodomain by a furin-like protease, and further complex glycosylation (7)(8)(9).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not matchedcites (7)(8)(9)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It is also found on the cell surface and cycles between the cell membrane and endosomes.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Examination of the FLIM images of transfected cells suggests that LRP and BACE interact (red pseudocolor) at the cell surface and in endosomal compartments.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Ectodomain shedding of LRP has been described (24)”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked — no full text of the sourcecites [24] Quinn, 1999, Exp. Cell Res. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Authenticity of the PCRgenerated constructs was confirmed by sequencing.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Generation of Expression Constructs of LRP and BACE and BACE
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus we now show that LRP is a substrate for both BACE and ␥-secretase, identified as APP-processing enzymes.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“After glycosylation, BACE co-traffics with APP and is rapidly transported to the Golgi apparatus and distal secretory pathway (9).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Abstract
What the sources say
- Not checked yetcites [9] Creemers, 2001, J. Biol. Chem. source
Checked before — its earlier verdict is held back until a new check runs.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not checked yet
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > Localization of BACE and LRP Constructs-We first tested the localization of BACE and LRP in co-expressing H4 cells.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Sialyltransferase and PSGL-1, in addition to APP and its homologues APLP1 and 2 are the only other reported substrates of BACE (6,43).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Not checked yetcites [46] Kawarabayashi, 2004, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“The LRP C-terminal domain also mediates an interaction with APP in similar cell compartments (22).”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > FIG. 9. BACE increases release of LRP-ICD.
What the sources say
- Not checked yetcites [22] Kinoshita, 2001, J. Neurosci. source
Checked before — its earlier verdict is held back until a new check runs.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Analogous results were obtained using three different fluorophores, multiple different antibody pairs, endogenous or transfected LRP and BACE, and two different cell types.”
§ The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel -Secretase (BACE1) Substrate* > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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).”
Citations
Cites
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
Purification and cloning of amyloid precursor protein β-secretase from human brain
Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., Davis, D., Doan, M., Dovey, H. F., Frigon, N., Hong, J., et al. (1999) · Nature · doi:10.1038/990114 · Cited by 1,612
Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity
Yan, R., Bienkowski, M. J., Shuck, M. E., Miao, H., Tory, M. C., Pauley, A. M., Brashler, J. R., Stratman, N. C., Mathews, W. R., Buhl, A. E., et al. (1999) · Nature · doi:10.1038/990107 · Cited by 1,438
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Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase
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Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex
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Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
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LRP: a multifunctional scavenger and signaling receptor
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Self-citationLRP: a multifunctional scavenger and signaling receptor
Herz, J., & Strickland, D. K. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113992 · Cited by 908
Self-citationA detergent-free method for purifying caveolae membrane from tissue culture cells.
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Cited by
Sorted by citations
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168
Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease
Bell, R. D., & Zloković, B. V. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0522-3 · Cited by 883
The secretases: enzymes with therapeutic potential in Alzheimer disease
De Strooper, B., Vassar, R., & Golde, T. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.218 · Cited by 799
Protein aggregation diseases: pathogenicity and therapeutic perspectives
Aguzzi, A., & O’Connor, T. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3050 · Cited by 766
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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