The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index; 27 of the 44 sources its claims cite were checked for support.
The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain
Open accessAbstract
Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β (Aβ) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
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TL;DR
The paper identifies sortilin as a major neuronal APOE receptor that mediates endocytic uptake and catabolism of APOE/Aβ complexes, thereby limiting brain Aβ accumulation and plaque burden. Sortilin deficiency in mice increases brain APOE and Aβ, aggravates early plaque burden, and causes APOE-deficiency-like sulfatide accumulation despite normal expression of other APOE receptors.
Key findings
- Sortilin binds all human APOE isoforms with high affinity (Kd = 117 nM for APOE2; 44 nM for APOE3; 114 nM for APOE4), but binds isolated Aβ40 poorly (Kd = 0.8 μM); neurotensin blocks APOE binding.
- In PDAPP and 5xFAD mice, Sort1 deletion increased brain Aβ40 (hippocampus and cortex at 5 and 9 months; 5xFAD at 2 months) and aggravated early plaque burden, without altering sAPPα/sAPPβ, C83/C99, or BACE1 activity.
- Sortilin-deficient mice showed a two-fold increase in hippocampal/cortical APOE with unchanged Apoe transcription and astrocyte secretion; primary sortilin-null neurons showed 70–80% reduced uptake of APOE/Aβ40 despite normal LRP1 and SORLA. CHO-mSort cells showed an approximate 5-fold increase in APOE3-bound Aβ40 uptake versus parental cells and 3-fold less uptake of free Aβ40.
- Sortilin-deficient mice had a two-fold increase in hippocampal sulfatide N24:1 at 5 months (also significant at 10 months), resembling Apoe−/− mice; LRP1 deficiency did not affect sulfatides at 5 months.
Methods
- Mouse models: Sort1−/− crossed with PDAPP and 5xFAD lines; conditional neuronal Lrp1 knockout using Nse-cre; Sorl1−/− and Apoe−/− mice; primary hippocampal neurons and cortical astrocytes.
- Binding and uptake: surface plasmon resonance/BIAcore with sortilin ectodomain and APOE2/3/4 proteoliposomes; CHO-mSort and HEK293 cells; confocal immunofluorescence, ELISA, Western blot, metabolic labeling, and quantitative RT-PCR.
- Lipid and pathology analysis: mass spectrometry for sulfatide N24:1; APP processing by ELISA/Western/BACE1 FRET; plaque burden by thioflavin S; statistics by Student’s t-test, Mann-Whitney U test, and one-way or two-way ANOVA with Bonferroni post hoc tests.
Limitations
- Stated: the authors cannot exclude that sortilin may also clear free Aβ in vivo; whether APOE3 versus APOE4 binding differences explain AD risk remains unresolved; molecular pathways of APOE-dependent brain sulfatide turnover are poorly understood.
- Evident from the text: findings rely on mouse models and cell lines rather than human tissue or clinical outcomes; the 5xFAD plaque effect was masked at 10 months; some uptake experiments use overexpression systems; sample sizes and sex are not reported in the provided text.
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Claims the paper makes
27 of 44 cited sources checked · 11 supported · 1 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APOE-containing lipoproteins extract sulfatides from the myelin sheath and deliver them to neurons for uptake and catabolism via APOE receptors (Han et al., 2003; Cheng et al., 2010).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
What the sources say
- Partly supportedcites Han et al., 2003 sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) says apoE-containing particles likely acquire most of their sulfatide from myelin and proposes transport and receptor-mediated recycling as pathways for its metabolism. It does not establish extraction from the myelin sheath or delivery specifically to neurons for uptake and catabolism; those steps are more definite and specific than the paper's proposed mechanism. (LLM, conf=0.88)
- Partly supportedcites Cheng et al., 2010 sourceExperimental — accuracy not yet measured
The Introduction describes a working model in which apoE-associated lipoproteins acquire sulfatides from myelin, then can be taken up and degraded by neurons through LDL-receptor-family pathways. The cited paper presents acquisition as likely and the neuronal pathway as a possibility, whereas the citing sentence states the entire process as established fact. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Accordingly, loss of APOE expression in Apoe−/− mice causes an approximate two-fold increase in brain sulfatide levels while overexpression of human APOE3 and APOE4 reduces the concentration of these lipids in mice (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
What the sources say
- Partly supportedcites Han et al., 2003 sourceExperimental — accuracy not yet measured
The Results report that, at 12 months, Apoe−/− mice had 114% more sulfatide in the cortex than wild-type mice—approximately a two-fold level. The increase was 61% in the hippocampus and 7% in the cerebellum, so the two-fold figure does not describe all measured brain regions. (LLM, conf=0.87)
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
“One of the main effects of altered APOE levels in mice is a change in brain sulfatide levels.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
What the sources say
- Supportedcites Han et al., 2003 source
The Results (page not provided) report that apoE-knockout mice had higher brain sulfatide content than wild-type mice, while mice expressing human apoE3 or apoE4 had lower levels in examined brain regions. The paper also reports no significant differences in several other examined lipids, supporting the characterization of sulfatide change as a main observed effect. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Accordingly, loss of APOE expression in Apoe−/− mice causes an approximate two-fold increase in brain sulfatide levels while overexpression of human APOE3 and APOE4 reduces the concentration of these lipids in mice (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
What the sources say
- Partly supportedcites Han et al., 2003 sourceExperimental — accuracy not yet measured
The Results report lower brain sulfatide levels in mice expressing human apoE3 or apoE4 than in wild-type mice. However, the paper describes these as transgenic mice, not mice overexpressing apoE: their human apoE levels were approximately 70% of mouse apoE levels in wild-type mice. (LLM, conf=0.86)
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
“In line with this notion, lower (rather than higher) sulfatide levels were observed in another mouse model with neuron-specific LRP1 deficiency previously (Liu et al., 2010).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Liu et al., 2010 source
The Results section (‘LRP1 expression is critical for brain lipid homeostasis’; page unavailable) reports significantly lower cortical sulfatide levels in mice with neuronal LRP1 deletion than in littermate controls at 12 months of age. This directly supports the attributed comparison. (LLM, conf=0.94)
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Experimental support for involvement of LDL receptors and LRP1 in brain APOE catabolism stems from the fact that inactivation of either Ldlr or Lrp1 causes accumulation of APOE in the brain of mice (Fryer et al., 2005; Liu et al., 2007).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Fryer et al., 2005 sourceExperimental — accuracy not yet measured
The Results report that Ldlr-knockout mice had 53% more apoE in CSF and 57% more in an extracellular pool of cortical tissue. The paper does not report brain apoE accumulation after Lrp1 inactivation in mice; its Lrp-knockout experiment used cultured fibroblasts, and the Discussion says LRP’s effect on brain apoE levels is difficult to assess. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Liu et al., 2007 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Loss of receptor expression in gene-targeted mice coincides with an increase in systemic APOE levels that parallels increases seen in the LDL receptor null mice (100% in Sort1−/− vs. 60% in Ldlr−/− lines) (Fig. 6A–B) (Fryer et al., 2005).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Fryer et al., 2005 sourceExperimental — accuracy not yet measured
The Results report elevated plasma apoE in Ldlr−/− mice and increases of 53% in CSF and 57% in cortical extracellular pools. Those CNS measurements are close to 60%, but the paper does not report a 60% increase in systemic apoE; it does not study Sort1−/− mice. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Although the molecular pathways involved in APOE-dependent turnover of brain sulfatides are poorly understood, levels of the apolipoprotein are typically inversely correlated with levels of these lipids (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Han et al., 2003 sourceExperimental — accuracy not yet measured
The Results report higher brain sulfatides in apoE-knockout mice than in wild-type mice, supporting an inverse relationship when apoE is absent versus present. They do not establish that apoE protein levels are typically inversely correlated with brain sulfatide levels: the Results also state that apoE3 and apoE4 transgenic mice express indistinguishable amounts of apoE but have different sulfatide levels. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Still, recent findings that pharmacological induction of Apoe expression in mice ameliorates Aβ production and plaque deposition strongly supports an inverse correlation of APOE concentration with brain Aβ levels (Cramer et al., 2012).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Cramer et al., 2012 sourceExperimental — accuracy not yet measured
The results passages (indexed under Abstract; page unavailable) report that bexarotene increased apoE expression and reduced soluble Aβ and plaque burden in treated mice. They attribute the fall in soluble Aβ to increased clearance, not reduced Aβ production. Plaque burden was also unchanged after three months of treatment, so the plaque finding does not hold across all treatment durations. (LLM, conf=0.90)
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While our data substantiate an important role for sortilin in amyloidogenic processes, they disagree with prior studies in cellular overexpression systems that argued for a direct role of this receptor in APP processing through regulation of β-secretase trafficking (Finan et al., 2011).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Finan et al., 2011 source
The Results report that sortilin overexpression in HEK293 cells increased BACE1-mediated cleavage of APP and suggest that sortilin affects APP processing by altering BACE1’s subcellular distribution. The Discussion likewise states that sortilin’s cytoplasmic domain can regulate BACE1 distribution and thereby affect APP processing. The citing authors’ disagreement is their own conclusion, not a claim attributed to Finan et al. (LLM, conf=0.94)
Strength:plain· 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
“However, one has to keep in mind that the concentration of Aβ applied to cells (0.7 μg/ml) is significantly higher than the amount of total Aβ detected, for example, in the PDAPP+/− mouse brain (<3 ng/ml) (Castellano et al., 2012).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Could not verifycites Castellano et al., 2012 sourceExperimental — accuracy not yet measured
The Results describe Aβ burden in PDAPP mouse brains as fold differences between groups, but do not give a total brain Aβ concentration of <3 ng/ml. Searches for that value and for 0.7 μg/ml found no passage supporting the numerical comparison; no page numbers were available in our copy. (LLM, conf=0.72)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Thus, while total levels of cholesterol remain unaltered (data not shown), loss of sortilin coincides with elevated hippocampal levels of sulfatides that are in the same order of magnitude as in APOE-deficient animals (two-fold) (Fig. 14) (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Han et al., 2003 source
The Results report that hippocampal sulfatide content in apoE-deficient mice was 61% higher than in wild-type mice at 12 months—approximately 1.6-fold, consistent with the citing sentence’s rough two-fold comparison. The sortilin finding is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Also, Deane et al. documented an affinity for Aβ binding to LRP1 (Kd=0.57 nM) that is a 1000-fold higher than the one determined for sortilin (Deane et al., 2004).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Deane et al., 2004 sourceExperimental — accuracy not yet measured
The Results (Figures 1A–1B; page not provided) report a Kd of 0.57 nM for Aβ40 binding to immobilized LRP cluster II. The paper does not report sortilin binding or a 1000-fold comparison, so that part of the attributed claim is unsupported. (LLM, conf=0.88)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Whereas the LDL receptor mainly mediates uptake of APOE into microglia and astrocytes (Kim et al., 2009), LRP1 constitutes an uptake pathway for this apolipoprotein in neurons (reviewed in (Holtzman et al., 2012)).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Kim et al., 2009 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) identifies LDLR as a major apoE receptor in the brain and reports that LDLR overexpression lowers brain apoE levels. It does not establish that LDLR mainly mediates apoE uptake specifically into microglia and astrocytes; the paper discusses those cells in relation to inflammation, not apoE uptake. (LLM, conf=0.85)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Support for a critical role for sortilin in systemic APOE metabolism stems from changes in lipid profiles in sortilin-deficient mice that recapitulate features shown for Apoe−/− animals before (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Partly supportedcites Han et al., 2003 sourceExperimental — accuracy not yet measured
The Results (page unavailable) show an altered lipid profile in Apoe−/− mice: brain sulfatide increased, while the other measured brain lipids did not differ significantly. That supports the reference to previously observed features of Apoe−/− animals, but the paper does not show that sortilin-deficient mice recapitulate them or establish a systemic lipid-profile comparison. (LLM, conf=0.84)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- 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
“Loss of receptor expression did not alter total brain levels of endogenous murine (Fig. 1A, B) or human APP (Fig. 1C, D) in these mice compared to controls.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“Sortilin binds APOE with high affinity.”
- Also stated in: § Sortilin acts as endocytic receptor for APOE · plain
“the extracellular domain of sortilin bound all three APOE isoforms (Kd = 117 nM for APOE2; 44 nM for APOE3; 114 nM for APOE4).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Sortilin acts as endocytic receptor for APOE · 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
“the increase in Aβ40 was not paralleled by corresponding changes in the levels of soluble (s) APPα or sAPPβ fragments in affected animals (Fig. 1E).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
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
“no signs of overt neuropathology were observable in histological brain sections from receptor null mice stained with thionine or antibodies directed against GFAP or NeuN, markers of glia cells and neurons, respectively (Fig. 5).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“At 5 months of age, sortilin-deficient animals exhibited a two-fold increase in levels of the major brain sulfatide variant N24:1 in the hippocampus.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
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
“Quantitative analysis by ELISA demonstrated an approximate 5-fold increase in uptake of APOE3-bound Aβ40 in CHO-mSort compared with parental CHO cells (Fig. 10B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“the rate of secretion of APOE from astrocytes, the main source of this apolipoprotein in the brain, was not affected by the absence of the receptor as shown by metabolic labeling experiments in primary astrocyte cultures (Fig. 7).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“In contrast to the situation with sortilin, deficiency for LRP1 did not affect the brain levels of sulfatides in mice with conditional inactivation of Lrp1 in neurons at 5 months of age (Fig. 14).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“no accumulation of APOE was seen in mice genetically deficient for Lrp1 or for Sorl1 in this study.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“efficient uptake of Aβ40 was seen in cells expressing sortilin when the amyloid peptide was complexed with lipidated APOE4 (CHO-mSort; Fig. 10A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“these cells exhibited a 70 – 80% reduction in uptake of exogenously added APOE/Aβ40 complexes as compared to wild-type cells (Fig. 13B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
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
“In the absence of exogenous APOE, the concentrations of sAPPα and sAPPβ (Fig. 13C), or of Aβ40 and Aβ42 (Fig. 13D) were not changed in sortilin-deficient compared to control neurons.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“a two-fold increase in the concentration of APOE in hippocampus and cortex of sortilin null mice was evident when determining protein levels by Western blot (Fig. 6A, B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
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
“Elevated levels of APOE were not due to an increased rate of transcription as demonstrated by quantitative RT-PCR of Apoe transcripts in hippocampal and cortical tissues of the respective animals (Fig. 6C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Load-bearingStrength:boosted· not yet calibratedTests✓ 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
“The plasma levels of Aβ40 were identical in (PDAPP+/−, Sort1−/−) and control animals (Fig. 4A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“the levels of the Aβ-degrading enzymes CD10 (neprilysin) (Iwata et al., 2001) and insulin degrading enzyme (IDE) (Farris et al., 2003) were not altered in the brain of receptor-deficient mice as shown by Western blot analyses (Fig. 4B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Load-bearingStrength:plain· 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
“Binding was significantly reduced by neurotensin, a neuropeptide that binds to the VPS10P domain and blocks interaction with ligands that target this receptor domain (Mazella et al., 1998; Quistgaard et al., 2009).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
Strength:plain· not yet calibratedCausal:direct· 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
“no uptake of free or APOE-bound HiLyte-Aβ40 was detectable in cells lacking receptor expression (CHO; Fig. 10A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
Load-bearingStrength:plain· 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
“mice carrying a targeted disruption of Sorl1 (Andersen et al., 2005) displayed similar levels of APOE in cortex as wild-type controls (Fig. 12E, F).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“poor binding to the sortilin ectodomain was seen for isolated Aβ40 (Fig. 8D; Kd = 0.8 μM).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
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
“Determination of Aβ40 levels in cell supernatants after 48 hours gave identical results for parental HEK293 (121.7 ± 13.62 pg Aβ/ng APP; n=11) and HEK293-mSort cells (99.87 ± 6.260 pg Aβ/ng APP; n=11; p=0.39 by Mann Whitney U test).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“At 10 months of age, the aggressive plaque burden observable in the 5xFAD model masked the consequences of sortilin deficiency on plaque deposition (Fig. 3B, C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Strength:plain· not yet calibratedCausal:direct· 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
“lack of sortilin resulted in a significant increase in Aβ40 levels in brain extracts of (PDAPP+/−, Sort1−/−) mice compared with (PDAPP+/−, Sort1+/+) controls (Fig. 1E).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
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
“avid internalization of all three human APOE isoforms was seen by immunofluorescence microscopy. Little APOE uptake was observed in parental CHO cells lacking the receptor (Fig. 9B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
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
“Internalized Aβ40 and APOE molecules co-localized with sortilin in intracellular compartments of the cells (Fig. 11A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“elevated levels of Aβ40 were seen in 5xFAD mice lacking sortilin (5xFAD, Sort1−/−) compared to control mice (5xFAD, Sort1+/+) at 2 months of age (Fig. 3A)”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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
“sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > 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
“levels of APOE in hippocampus and cortex of the LRP1-deficent mice were not altered as compared to matched controls as shown by Western blotting (Fig. 12C) and by densitometric scanning thereof (Fig. 12D).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
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
“Cellular uptake of APOE-bound Aβ40 was reduced by the receptor antagonists GST-pro and neurotensin (Fig. 10C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“A rise in Aβ40 levels in (PDAPP+/−, Sort1−/−) mice was seen both in the hippocampus and in the cortex at 5 months (Fig. 1F) and at 9 months of age (Fig. 1G).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“Levels of transcripts encoding SORLA, LRP1, LDL receptor, VLDL receptor, LRP8, or SORCS1, -2, and -3 were unchanged in the cortex of sortilin-deficient compared to wild-type mice as documented by quantitative RT-PCR analyses (Fig. 12B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“Comparative quantitative RT-PCR analysis revealed transcript levels for Sort1 and Sorl1 (the gene encoding SORLA) in the murine cortex that were 10- and 20-fold higher than those for Lrp1, arguing for high levels of sortilin (and SORLA) expression in the brain (Fig. 12A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
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
“A significant increase in brain sulfatides was also confirmed at 10 months of age (Fig. 14).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
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
“no sortilin-mediated uptake of HiLyte-Aβ was seen in APOE-free HDL.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“resulted in an aggravated plaque burden as documented by thioflavin S staining of hippocampal sections (Fig. 3B, C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
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
“3-fold less uptake was seen in CHO-mSort cells incubated with free Aβ40 as compared to APOE3-bound Aβ40, substantiating the ability of APOE to promote sortilin-dependent clearance of the peptide (Fig. 10B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“Unimpaired proteolytic activity in the sortilin-deficient mouse brain was substantiated by Western blot analysis of carboxyl terminal fragments C83 and C99, the products of α- and β-secretases, respectively (Fig. 2A, B), and by determination of BACE1 activity using FRET assay (Castellano et al., 2011) (Fig. 2C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Load-bearingStrength:boosted· not yet calibratedTests✓ 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
“In this study, we observed low affinity binding of Aβ to sortilin in BIAcore (Fig. 8) and some residual uptake of the free peptide in CHO-mSort cells (Fig. 10A–B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“However, we noticed a two-fold lower Kd for binding of APOE3 (44 nM) versus APOE4 (114 nM) (Fig. 8).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“In addition, accumulation of brain sulfatides was seen in sortilin- but not in LRP1-deficient animals in this study (Fig. 14).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Also, transcript levels of members of the LDL receptor and VPS10P-domain receptor gene families were not affected by sortilin deficiency (Fig. 12B), strongly arguing for a direct effect of sortilin on APOE and Aβ turnover in vivo.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“Most importantly, sortilin mediates cellular uptake of Aβ bound to APOE (Fig. 10) and receptor deficiency results in accumulation of Aβ peptides and in increased plaque burden in two AD mouse models (Figs. 1 and 3).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > 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
“Data obtained so far also failed to identify obvious differences in cellular handling of APOE3 versus APOE4 by sortilin.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Thus, while total levels of cholesterol remain unaltered (data not shown), loss of sortilin coincides with elevated hippocampal levels of sulfatides that are in the same order of magnitude as in APOE-deficient animals (two-fold) (Fig. 14) (Han et al., 2003).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“In this study, we observed low affinity binding of Aβ to sortilin in BIAcore (Fig. 8) and some residual uptake of the free peptide in CHO-mSort cells (Fig. 10A–B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Surprisingly, APOE-dependent uptake of Aβ was impaired in primary neurons lacking sortilin despite normal levels of LRP1 and SORLA (Fig. 13).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > 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
“Most importantly, sortilin mediates cellular uptake of Aβ bound to APOE (Fig. 10) and receptor deficiency results in accumulation of Aβ peptides and in increased plaque burden in two AD mouse models (Figs. 1 and 3).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > 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
“Also, neurotensin blocked receptor interaction with APOE3 much more efficiently than with APOE4 (80% versus 30% inhibition, respectively) (Fig. 8).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Strength:plain· not yet calibratedCausal:direct· 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
“In support of our model, no accumulation of APOE was seen in mice lacking SORLA or LRP1 in this study (Fig. 12C–F).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“In contrast to Aβ, the levels of other soluble or membrane-tethered APP processing products are not affected by receptor deficiency (Figs. 1, 2, and 13C).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ 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
“Most importantly, sortilin mediates cellular uptake of Aβ bound to APOE (Fig. 10) and receptor deficiency results in accumulation of Aβ peptides and in increased plaque burden in two AD mouse models (Figs. 1 and 3).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“our data argued for a role of sortilin in catabolism of amyloid-β peptides in the brain.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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
“our data argued for impaired cellular uptake of APOE as the cause of Aβ accumulation and deposition in the brain of sortilin-deficient mice.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin impairs neuronal catabolism of APOE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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
“Sortilin is a major APOE receptor in neurons”
- Also stated in: § Abstract · plain
“identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
- Also stated in: § Abstract · plain
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 conclusion, our findings have identified a hitherto unknown function for sortilin as neuronal APOE receptor in the brain and they uncovered APOE-dependent clearance as a molecular mechanism of receptor action in AD.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
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 finding suggested an effect of receptor activity on time of onset and early progression of amyloidosis.”
- Also stated in: § Loss of sortilin increases brain Aβ levels in mice · plain
“accelerated onset of senile plaques deposition.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Loss of sortilin increases brain Aβ levels in mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Loss of sortilin increases brain Aβ levels in mice · plain
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
“our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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 conclusion, our findings have identified a hitherto unknown function for sortilin as neuronal APOE receptor in the brain and they uncovered APOE-dependent clearance as a molecular mechanism of receptor action in AD.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
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
“So far, our data indicated a major role for sortilin as APOE receptor in neurons.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
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
“indicating functional deficiency in cellular APOE uptake pathways.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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
“suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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
“Co-localization of Aβ40 with the marker cathepsin B suggested predominant lysosomal targeting of the internalized peptides (Fig.11B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin mediates cellular uptake of Aβ bound to APOE
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
“Thus, sortilin activity does not impact the rate of Aβ production or clearance in neurons when APOE is absent.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin is a major APOE receptor in neurons
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
“Now, our studies identified sortilin as another APOE receptor to be considered in this context.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Also, transcript levels of members of the LDL receptor and VPS10P-domain receptor gene families were not affected by sortilin deficiency (Fig. 12B), strongly arguing for a direct effect of sortilin on APOE and Aβ turnover in vivo.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“These observations point towards an isoform-specific interaction of sortilin with human APOE.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Intriguingly, our studies now uncovered the relevance of this receptor pathway in control of lipoprotein homeostasis in the brain as well.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Obviously, many of these data are inconsistent with a simple role for LRP1 in neuronal APOE/Aβ clearance.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Load-bearingStrength:boosted· 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
“All evidence in this study is consistent with a model whereby sortilin represents a major neuronal receptor pathway for APOE-containing lipoproteins that counteracts Aβ accumulation in the brain.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Because expression of sortilin in the CNS is restricted to neurons (Sarret et al., 2003), we assessed the quantitative contribution of this receptor pathway to neuronal APOE/Aβ catabolism.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Sarret et al., 2003 source
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
“While our data substantiate an important role for sortilin in amyloidogenic processes, they disagree with prior studies in cellular overexpression systems that argued for a direct role of this receptor in APP processing through regulation of β-secretase trafficking (Finan et al., 2011).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“These data strongly argue for a defect in neuronal clearance of APOE-containing lipoproteins (and associated sulfatides) in mice lacking this receptor.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Thus, this receptor represents a pathway where pro-neurotrophin signaling, Aβ catabolism, and brain lipoprotein metabolism converge.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“In conclusion, our studies have identified the pro-neurotrophin receptor sortilin as a major neuronal pathway involved in brain APOE and Aβ metabolism.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Regardless of possible differences in handling of APOE3 versus APOE4, the ability of sortilin to modulate brain lipid and APOE homeostasis strongly implicates this receptor pathway in pathophysiological mechanisms whereby alterations in brain lipoprotein metabolism affect the risk of sporadic AD.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Sortilin-mediated endocytosis likely results in lysosomal degradation of the amyloid-β peptides (Fig. 11B).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 18
- It may state two separate claims as one. 11
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“The underlying mechanism was traced to the ability of sortilin to act as intracellular sorting receptor for APOB100 and to facilitate release of nascent APOB100-containing lipoproteins from the liver (Kjolby et al., 2010; Musunuru et al., 2010).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Kjolby et al., 2010 source
- Disputedcites Musunuru et al., 2010 sourceExperimental — accuracy not yet measured
The paper describes sortilin as an intracellular sorting receptor, but its results contradict the claimed effect on release. In “Sort1 in Mouse Liver Alters Plasma Lipids” (page unavailable), Sort1 overexpression decreased VLDL secretion and apoB-100 secretion from hepatocytes, while knockdown increased apoB-100 secretion. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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
“Due to the premature lethality of mice with brain-specific LRP1 deficiency (May et al., 2004), sulfatide levels could not be evaluated at later stages in this line.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
What the sources say
- Supportedcites May et al., 2004 source
The Results report that SynCre/LRPlox/lox mice, which lack LRP1 in differentiated neurons, die prematurely around 9 months of age; the Discussion also attributes their premature death to the mutant phenotype. The citation supports the lethality premise. The statement about not evaluating sulfatide levels at later stages is the citing authors’ own consequence, not a finding attributed to this paper. (LLM, conf=0.93)
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
“APOE is the most important genetic risk factor for sporadic AD (Corder et al., 1993; Strittmatter et al., 1993).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Corder et al., 1993 source
- Partly supportedcites Strittmatter et al., 1993 sourceExperimental — accuracy not yet measured
The paper reports a significant association between APOE-e4 and late-onset familial Alzheimer disease (allele-association results; page not available). It says a separate report will address sporadic Alzheimer disease, and it does not rank APOE against other genetic risk factors. Thus it supports a genetic association, but not the claim's sporadic population or “most important” qualifier. (LLM, conf=0.89)
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.
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
“In the brain, endocytic pathways in glia cells (likely the LDL receptor) and in neurons are implicated in cellular catabolism of APOE/Aβ complexes (Koistinaho et al., 2004; Jiang et al., 2008; Holtzman et al., 2012).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Koistinaho et al., 2004 source
- Not checked — no full text of the sourcecites Jiang et al., 2008 source
- Supportedcites Holtzman et al., 2012 source
The section “LRP1 and LDLR in Cellular and Brain Aβ Metabolism” (page unavailable) describes receptor-mediated Aβ uptake by astrocytes, microglia, and neurons, with LDLR among the implicated receptors. Figure 4’s caption describes endocytosis of apoE/lipoprotein/Aβ complexes and delivery to lysosomes for degradation. The paper cautions that some Aβ taken up by neurons can accumulate instead, consistent with the claim’s qualified wording, “implicated.” (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Data from transgenic mouse models produced more conflicting results with impaired plaque deposition seen in mice lacking murine APOE (Bales et al., 1997; Holtzman et al., 2000), but also in animals overexpressing the human APOE3 or APOE4 isoforms (Holtzman et al., 1999).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Bales et al., 1997 source
- Supportedcites Holtzman et al., 2000 source
The Results section reports reduced hippocampal Aβ deposition in mice lacking apoE compared with mice expressing murine apoE. It also reports that later deposits in apoE-deficient mice were largely nonfibrillar, so impaired plaque deposition does not mean that deposition was absent. The human-apoE clause is attributed to a different citation. (LLM, conf=0.92)
- Partly supportedcites Holtzman et al., 1999 sourceExperimental — accuracy not yet measured
The Results report markedly less Aβ deposition in mice expressing human apo E3 or apo E4, supporting the finding attributed to Holtzman et al. (1999). But the Introduction describes these mice as expressing physiological levels of human apo E, not overexpressing it. The paper also reports reduced deposition in mice lacking murine apo E, though the citing sentence assigns that finding to other references. (LLM, conf=0.88)
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.
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
“Likely, the multiple alternative functions assigned to this receptor in AD, including intracellular APP transport (Ulery et al., 2000; Pietrzik et al., 2002), blockade of APP signaling (Kinoshita et al., 2003), or Aβ shunt across the blood-brain-barrier (Deane et al., 2004) complicate interpretation of the available experimental data.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Ulery et al., 2000 source
The cited Ulery et al. paper supports the part of the sentence attached to it: it proposes that LRP–APP interaction modulates APP trafficking within the endocytic pathway (discussion following Fig. 4; page not provided). The statement that multiple functions complicate interpretation is the citing authors’ framing, not a conclusion attributed specifically to Ulery et al. (LLM, conf=0.90)
- Supportedcites Pietrzik et al., 2002 source
Pietrzik et al. support the part of the citing sentence attached to their citation: LRP's role in intracellular APP trafficking. The Discussion states that LRP affects APP trafficking, and the section “Abnormalities in APP processing are isoform independent” identifies a functional role for APP and LRP in that trafficking. The claim that multiple roles complicate interpretation is the citing authors' conclusion, not a finding attributed specifically to this paper. (LLM, conf=0.92)
- Not checked yetcites Kinoshita et al., 2003 source
Checked before — its earlier verdict is held back until a new check runs.
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.
- 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
“Conversely, overexpression of the LDL receptor (Kim et al., 2009) or of LRP1 mini receptors reduces systemic levels of APOE in the CNS (Zerbinatti et al., 2006).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Kim et al., 2009 source
The Results section reports that LDLR-overexpressing mice had significantly lower apoE protein levels in cortical and hippocampal tissue. Kim et al. (2009) is cited for the LDLR portion of the sentence; the LRP1 mini-receptor portion has a separate citation. The paper measures apoE in the brain, not in the systemic circulation. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites Zerbinatti et al., 2006 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. 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
“One common hypothesis states that APOE sequesters soluble Aβ in the extracellular space resulting in cellular uptake and catabolism of this neurotoxic peptide. This hypothesis is supported by many in vitro studies (Koistinaho et al., 2004; Morikawa et al., 2005; Jiang et al., 2008).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Koistinaho et al., 2004 source
- Partly supportedcites Morikawa et al., 2005 sourceExperimental — accuracy not yet measured
The ‘Interaction of astrocyte-secreted apoE with Aβ’ section (page not available) reports that soluble Aβ associated with apoE-containing particles in vitro, supporting the sequestration part of the hypothesis. The paper discusses apoE’s role in Aβ clearance, but its reported interaction experiments do not show that the bound peptide undergoes cellular uptake or catabolism. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Jiang et al., 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Whereas the LDL receptor mainly mediates uptake of APOE into microglia and astrocytes (Kim et al., 2009), LRP1 constitutes an uptake pathway for this apolipoprotein in neurons (reviewed in (Holtzman et al., 2012)).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Supportedcites Holtzman et al., 2012 source
The section “Evidence that LRP1 and LDLR Are Key Metabolic Receptors for ApoE/Lipoprotein in the Brain” (page unavailable) identifies LRP1 as a primary metabolic receptor for apoE/lipoprotein and reports that deleting Lrp1 in mouse forebrain neurons increases brain apoE levels. It also says LRP1 is highly expressed in neurons; another passage describes apoE/lipoprotein binding to LRP1 at the neuronal cell surface. Together, these support the review citation for neuronal uptake. (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.
- Supported
None of the sources cited for this claim have been checked yet.
In the paper
“sortilin efficiently internalized ligands as shown for GST-pro, a surrogate ligand composed of the pro-domain of proNGF (the sortilin binding site) fused to glutathione-S transferase (Nykjaer et al., 2004) (Fig. 9A).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
Strength:boosted· 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 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 receptor mainly localized to intracellular compartments in CHO-mSort cells, in line with what has been observed in other cell types before (Fig. 9A) (Nielsen et al., 2001).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
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 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
“our data revealed that sortilin does not affect APP processing in cells or in vivo.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > INRODUCTION
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
“Co-localization of receptor and ligands at the cell surface of non-permeabilized cells was readily visible for both APOE3 (Fig. 9D) and APOE4 (Fig. 9E).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Sortilin acts as endocytic receptor for APOE
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
“Sortilin-deficient animals exhibit elevated sulfatide concentrations albeit at higher than normal levels of APOE.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > 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
“Sortilin binds and mediates cellular uptake of all human APOE isoforms (Figs. 9–11).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
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
“Rather, it acts as an APOE receptor in neurons, constituting a major endocytic pathway for catabolism of Aβ bound to this apolipoprotein in the brain.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > INRODUCTION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
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
“Absence of this receptor recapitulates features seen in mice lacking APOE (such as accumulation of brain sulfatides) despite higher than normal levels of the apolipoprotein in the CNS.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Thus, we cannot exclude that sortilin may also clear free Aβ in vivo.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
Strength:hedged· not yet calibratedCausal:conditional· 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 the central nervous system, this 34-kDa protein is mainly produced by microglia and astrocytes (Pitas et al., 1987) and delivers cholesterol-rich lipoproteins to neurons to support synaptogenesis and maintenance of synaptic connections (Mauch et al., 2001).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Mauch et al., 2001 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
“Because other neuronal APOE receptors seemed properly expressed in sortilin-deficient mice, our data suggest that sortilin represents a pathway of major quantitative importance for neuronal clearance of APOE-containing lipoproteins and APOE/Aβ complexes.”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > RESULTS > Lipid profiles in sortilin-deficient mice recapitulate features of murine APOE deficiency
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Finally, neuron-specific inactivation of Lrp1 was shown to decrease (Liu et al., 2007) while overexpression of a LRP1 mini receptor to increase brain Aβ levels (Zerbinatti et al., 2006).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Liu et al., 2007 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.
In the paper
“Recently, sortilin was identified as a genetic risk factor in cardiovascular disease associated with high plasma cholesterol levels and occurrence of myocardial infarction in the human population (Kathiresan et al., 2009).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not matchedcites Kathiresan et al., 2009
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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 matched
In the paper
“A related role for sortilin as neuronal clearance receptor has recently been shown for progranulin, a protein implicated in frontotemporal lobar degeneration (Hu et al., 2010).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not matchedcites Hu et al., 2010
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.
- Not matched
In the paper
“Finally, neuron-specific inactivation of Lrp1 was shown to decrease (Liu et al., 2007) while overexpression of a LRP1 mini receptor to increase brain Aβ levels (Zerbinatti et al., 2006).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Zerbinatti et al., 2006 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.
In the paper
“In the central nervous system, this 34-kDa protein is mainly produced by microglia and astrocytes (Pitas et al., 1987) and delivers cholesterol-rich lipoproteins to neurons to support synaptogenesis and maintenance of synaptic connections (Mauch et al., 2001).”
§ The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Pitas et al., 1987 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.
The paper relies on this without support.
APOE is the major risk factor for sporadic Alzheimer disease.
“Apolipoprotein (APO) E is the major risk factor for sporadic Alzheimer disease.”
The paper relies on this without support.
APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.
“Among other functions, APOE is proposed to sequester neurotoxic amyloid-β peptides (Aβ) in the brain, delivering them to cellular catabolism via neuronal APOE receptors.”
The paper relies on this without support.
The receptors involved in APOE/Aβ catabolism remain controversial.
“Still, the receptors involved in this process remain controversial.”
The paper relies on this without support.
Studies on the role of sortilin in AD have so far solely relied on in vitro studies.
“Although intriguing, studies on the role of sortilin in AD have so far solely relied on in vitro studies.”
The paper relies on this without support.
Astrocytes are the main source of APOE in the brain.
“astrocytes, the main source of this apolipoprotein in the brain”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Recently, we showed that sortilin also acts as a lipoprotein receptor in the brain, facilitating neuronal uptake of apolipoprotein E (apoE), the major carrier for lipids in brain interstitial fluids10.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [10]
In the citing paper
“Loss of PUFAs is attributed to a prominent role of the receptor in neuronal uptake of lipidated apoE, providing essential lipids for cellular lipid metabolism and action10,14.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [10]
In the citing paper
“Sortilin deficiency also reduces apoE uptake in primary mouse neurons by approximately 70%10.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [10]
In the citing paper
“Loss of sortilin activity in gene-targeted mice increases circulating levels of apoE in the brain, due to impaired cellular clearance of the carrier10.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [10]
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 1×
“Sortilin is expressed in neurons of the CNS and PNS but also in extraneuronal tissues, including liver and fat (Petersen et al., 1997; Morris et al., 1998; Sarret et al., 2003; Kjolby et al., 2010).”
BackgroundAlzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516
Plump, A. S., Smith, J. D., Hayek, T., Aalto-Setälä, K., Walsh, A., Verstuyft, J. G., Rubin, E. M., & Breslow, J. L. (1992) · Cell · doi:10.1016/0092-8674(92)90362-g · Cited by 2,263
CNS synaptogenesis promoted by glia-derived cholesterol
Mauch, D. H., Nägler, K., Schumacher, S., Göritz, C., Müller, E.-C., Otto, A., & Pfrieger, F. W. (2001) · Science · doi:10.1126/science.294.5545.1354 · Cited by 1,711
Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., & Guénette, S. Y. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0230450100 · Cited by 1,526
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242 · cited 1×
“2 A, B), and by determina- tion of BACE1 activity using FRET assay (Castellano et al., 2011) (Fig.”
MethodFrom noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., et al. (2010) · Nature · doi:10.1038/nature09266 · Cited by 1,140
Myocardial Infarction Genetics Consortium (2009) · Nature Genetics · doi:10.1038/ng.327 · Cited by 1,088
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Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158
Self-citationQiu, S., Palavicini, J. P., Wang, J., Gonzalez, N. S., He, S., Dustin, E., Zou, C., Ding, L., Bhattacharjee, A., Skike, C. E. V., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00488-7 · Cited by 126
Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity
Smith, L. M., & Strittmatter, S. M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024075 · Cited by 109
Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches
Sun, Y.-Y., Wang, Z., & Huang, H. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01365-1 · Cited by 102
Metadata
- Authors
- Carlo, A.-S., Gustafsen, C., Mastrobuoni, G., Nielsen, M. S., Burgert, T., Hartl, D., Rohe, M., Nykjaer, A., Herz, J., Heeren, J., Kempa, S., Petersen, C. M., & Willnow, T. E.
- Affiliations
- Max Delbrück Center (DE)
- Aarhus University (DK)
- Charité – Universitätsmedizin Berlin (DE)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-01-02
- Volume
- 33
- Issue
- 1
- Pages
- 358-370
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3744345
- OpenAlex
- W2095307581
- Cited by
- 117
- References
- 63
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 12 · 2018: 6 · 2017: 11 · 2016: 9 · 2015: 8 · 2014: 10 · 2013: 11
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- American Health Assistance Foundation
- European Commission
- Bundesministerium für Bildung und Forschung
- Lundbeckfonden (R54-2010-5281, R62-2010-5361)
- National Heart, Lung, and Blood Institute (R01HL063762, R37HL063762, P01HL020948)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- sortilin, apolipoprotein E, Alzheimer's disease, endocytosis, sulfatide, brain lipid metabolism, amyloid plaques, lipoprotein uptake
- MeSH terms
- Sortilin, Animals, Apolipoproteins E, Astrocytes, Brain, Neurons, Amyloid beta-Peptides, Low Density Lipoprotein Receptor-Related Protein-1, Adaptor Proteins, Vesicular Transport, Mice, Plaque, Amyloid
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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