The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index; 26 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.
Overview
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Written from the paper’s full text.
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
26 of 44 cited sources checked · 10 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
- 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 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.
None of the sources cited for this claim have been checked 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Flagged first, then by citations
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Items 101–117 of 117
Role of CD63 in the biogenesis and the function of exosomes
Palmulli, R. (2019) · theses.fr (ABES) · doi:10.70675/bf9b07cbz66d2z4a12zbbb1zfa2d8f83bdb6
Transmembrane domain interactions underlie NSG1 regulation of sortilin ectodomain shedding
Overby, M., Desdorf, L. M., Kjølbye, L. R., Rosendahl, T., Weick, J. P., Schiøtt, B., Berglund, N. A., & Müller, H. K. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110804
Pashova, S., Petrov, P. V., Karachanak-Yankova, S., Belezhanska, D., Zhelev, Y., Mehrabian, S., Toncheva, D. I., Traykov, L., & Pashov, A. D. (2025) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2025.578775
Qiu, 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) · Figshare · doi:10.6084/m9.figshare.16625144
Qiu, 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) · Figshare · doi:10.6084/m9.figshare.16625141
Fonction des neurotrophines et de la neurotensine dans l'oncogénèse lymphocytaire B
Saada, S. (2015) · theses.fr (ABES) · doi:10.70675/3f4863d1z280az4e70z9199zffb0b80a6f6b
Hivelin, C. (2016) · theses.fr (ABES) · doi:10.70675/12e87c26z74c5z4ecaz93d0zad569560ff37
Ramos, A. B. M. F. M., & Morais, V. A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27136073
Tau spreading coordinates intercellular lipid flux enhancing neuronal resilience to lipid toxicityPreprint
Oliveras, A., Ibatici, D., Calvo‐Noriega, M., Mastrobuoni, G., Forbes, M., Padilla, L. S., Aykul, M., Horvatović, K., Rusu, M.-C., Patsonis, M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.30.741734
Self-citationWNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signalingPreprint
Jaykumar, A. B., Binns, D. D., Taylor, C. A., Anselmo, A. N., Kankanamalage, S. G., Birnbaum, S. G., Huber, K. M., & Cobb, M. H. (2026) · eLife · doi:10.7554/elife.100097.3
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.
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