The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain

APOE-containing lipoproteins extract sulfatides from the myelin sheath and deliver them to neurons for uptake and catabolism via APOE receptors.

“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).”

• cites Han et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Cheng et al., 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Loss of APOE expression in Apoe−/− mice causes an approximate two-fold increase in brain sulfatide levels.

“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).”

• cites Han et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Altered APOE levels in mice cause changes in brain sulfatide levels.

“One of the main effects of altered APOE levels in mice is a change in brain sulfatide levels.”

• cites Han et al., 2003 sourceSupported

Overexpression of human APOE3 and APOE4 reduces brain sulfatide concentration in mice.

“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).”

• cites Han et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Inactivation of either Ldlr or Lrp1 causes accumulation of APOE in the brain of mice.

“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).”

• cites Fryer et al., 2005 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Liu et al., 2007 sourceNot checked — no full text of the source

Levels of APOE are typically inversely correlated with levels of brain sulfatides.

“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).”

• cites Han et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

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.

“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).”

• cites Cramer et al., 2012 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Our data disagree with prior studies that argued for a direct role of sortilin in APP processing through regulation of β-secretase trafficking.

“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).”

• cites Finan et al., 2011 sourceSupported

The concentration of Aβ applied to cells (0.7 μg/ml) is significantly higher than the amount of total Aβ detected in the PDAPP+/− mouse brain (<3 ng/ml).

“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).”

• cites Castellano et al., 2012 sourceCould not verify

  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)

  Experimental — accuracy not yet measured

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).

“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).”

• cites Han et al., 2003 sourceSupported

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.

“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).”

• cites Deane et al., 2004 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

The LDL receptor mainly mediates uptake of APOE into microglia and astrocytes.

“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)).”

• cites Kim et al., 2009 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

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.

“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).”

• cites Han et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Loss of sortilin does not alter total brain levels of endogenous murine or human APP in PDAPP mice.

“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.”

Sortilin binds APOE2, APOE3, and APOE4 with high affinity (Kd = 117 nM, 44 nM, and 114 nM, respectively).

“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 increase in Aβ40 in sortilin-deficient PDAPP mice was not paralleled by changes in soluble APPα or sAPPβ fragments.

“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).”

No signs of overt neuropathology were observable in histological brain sections from sortilin null mice stained with thionine or antibodies against GFAP or NeuN.

“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).”

At 5 months of age, sortilin-deficient animals exhibit a two-fold increase in levels of the major brain sulfatide variant N24:1 in the hippocampus.

“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.”

Quantitative ELISA demonstrated an approximate 5-fold increase in uptake of APOE3-bound Aβ40 in CHO-mSort compared with parental CHO cells.

“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 rate of secretion of APOE from astrocytes was not affected by absence of sortilin.

“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).”

Deficiency for LRP1 does not affect brain levels of sulfatides in mice with conditional inactivation of Lrp1 in neurons at 5 months of age.

“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).”

No accumulation of APOE was seen in mice genetically deficient for Lrp1 or for Sorl1 in this study.

“no accumulation of APOE was seen in mice genetically deficient for Lrp1 or for Sorl1 in this study.”

Sortilin mediates cellular uptake of Aβ40 when bound to APOE.

“efficient uptake of Aβ40 was seen in cells expressing sortilin when the amyloid peptide was complexed with lipidated APOE4 (CHO-mSort; Fig. 10A).”

Primary neurons from sortilin-deficient mice exhibited a 70-80% reduction in uptake of exogenously added APOE/Aβ40 complexes compared to wild-type cells, despite normal expression of LRP1 and SORLA.

“these cells exhibited a 70 – 80% reduction in uptake of exogenously added APOE/Aβ40 complexes as compared to wild-type cells (Fig. 13B).”

In the absence of exogenous APOE, concentrations of sAPPα and sAPPβ or Aβ40 and Aβ42 were not changed in sortilin-deficient compared to control neurons.

“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.”

A two-fold increase in APOE concentration in hippocampus and cortex of sortilin null mice.

“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).”

Elevated APOE levels in sortilin null mice were not due to increased transcription.

“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).”

Plasma levels of Aβ40 were identical in (PDAPP+/−, Sort1−/−) and control animals.

“The plasma levels of Aβ40 were identical in (PDAPP+/−, Sort1−/−) and control animals (Fig. 4A).”

Levels of Aβ-degrading enzymes CD10 (neprilysin) and IDE were not altered in the brain of sortilin-deficient mice.

“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).”

Binding of sortilin to APOE is significantly reduced by neurotensin.

“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).”

No uptake of free or APOE-bound HiLyte-Aβ40 was detectable in cells lacking receptor expression.

“no uptake of free or APOE-bound HiLyte-Aβ40 was detectable in cells lacking receptor expression (CHO; Fig. 10A).”

Mice carrying targeted disruption of Sorl1 displayed similar levels of APOE in cortex as wild-type controls.

“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).”

Sortilin binds isolated Aβ40 poorly (Kd = 0.8 μM).

“poor binding to the sortilin ectodomain was seen for isolated Aβ40 (Fig. 8D; Kd = 0.8 μM).”

Sortilin does not affect cellular Aβ40 production, as HEK293-mSort and parental HEK293 cells had identical Aβ40 levels.

“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).”

At 10 months of age, the aggressive plaque burden in 5xFAD model masked the consequences of sortilin deficiency on plaque deposition.

“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).”

Lack of sortilin results in a significant increase in Aβ40 levels in brain extracts of (PDAPP+/−, Sort1−/−) mice compared with (PDAPP+/−, Sort1+/+) controls.

“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).”

Sortilin mediates endocytic uptake of APOE2, APOE3, and APOE4 in CHO-mSort cells.

“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).”

Internalized Aβ40 and APOE molecules co-localized with sortilin in intracellular compartments.

“Internalized Aβ40 and APOE molecules co-localized with sortilin in intracellular compartments of the cells (Fig. 11A).”

Elevated levels of Aβ40 were seen in 5xFAD mice lacking sortilin compared to control 5xFAD mice at 2 months of age.

“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)”

Sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice.

“sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice”

Levels of APOE in hippocampus and cortex of LRP1-deficient mice were not altered compared to matched controls.

“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).”

Cellular uptake of APOE-bound Aβ40 was reduced by receptor antagonists GST-pro and neurotensin.

“Cellular uptake of APOE-bound Aβ40 was reduced by the receptor antagonists GST-pro and neurotensin (Fig. 10C).”

A rise in Aβ40 levels in (PDAPP+/−, Sort1−/−) mice was seen both in hippocampus and cortex at 5 months and at 9 months of age.

“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).”

Levels of transcripts encoding SORLA, LRP1, LDL receptor, VLDL receptor, LRP8, SORCS1, -2, and -3 were unchanged in the cortex of sortilin-deficient compared to wild-type mice.

“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).”

Transcript levels for Sort1 and Sorl1 in murine cortex were 10- and 20-fold higher than those for Lrp1.

“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).”

A significant increase in brain sulfatides in sortilin-deficient animals was confirmed at 10 months of age.

“A significant increase in brain sulfatides was also confirmed at 10 months of age (Fig. 14).”

No sortilin-mediated uptake of HiLyte-Aβ was seen in APOE-free HDL.

“no sortilin-mediated uptake of HiLyte-Aβ was seen in APOE-free HDL.”

Lack of sortilin in 5xFAD mice resulted in aggravated plaque burden at 2 months.

“resulted in an aggravated plaque burden as documented by thioflavin S staining of hippocampal sections (Fig. 3B, C).”

3-fold less uptake was seen in CHO-mSort cells incubated with free Aβ40 as compared to APOE3-bound Aβ40.

“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).”

Proteolytic activity in the sortilin-deficient mouse brain was unimpaired, as shown by Western blot of C83 and C99 and BACE1 activity.

“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).”

We observed some residual uptake of free Aβ in CHO-mSort cells.

“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).”

We noticed a two-fold lower Kd for binding of APOE3 (44 nM) versus APOE4 (114 nM).

“However, we noticed a two-fold lower Kd for binding of APOE3 (44 nM) versus APOE4 (114 nM) (Fig. 8).”

Accumulation of brain sulfatides was seen in sortilin- but not in LRP1-deficient animals in this study.

“In addition, accumulation of brain sulfatides was seen in sortilin- but not in LRP1-deficient animals in this study (Fig. 14).”

Transcript levels of members of the LDL receptor and VPS10P-domain receptor gene families were not affected by sortilin deficiency.

“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.”

Receptor deficiency results in increased plaque burden in two AD mouse models.

“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).”

Loss of sortilin expression in gene-targeted mice coincides with an increase in systemic APOE levels that parallels increases seen in LDL receptor null mice (100% in Sort1−/− vs. 60% in Ldlr−/− lines).

“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).”

• cites Fryer et al., 2005 sourceNot checked yet

Data obtained so far failed to identify obvious differences in cellular handling of APOE3 versus APOE4 by sortilin.

“Data obtained so far also failed to identify obvious differences in cellular handling of APOE3 versus APOE4 by sortilin.”

Total levels of cholesterol remain unaltered in sortilin-deficient mice.

“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).”

We observed low affinity binding of Aβ to sortilin in BIAcore.

“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).”

APOE-dependent uptake of Aβ was impaired in primary neurons lacking sortilin despite normal levels of LRP1 and SORLA.

“Surprisingly, APOE-dependent uptake of Aβ was impaired in primary neurons lacking sortilin despite normal levels of LRP1 and SORLA (Fig. 13).”

Sortilin mediates cellular uptake of Aβ bound to APOE.

“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).”

Neurotensin blocked receptor interaction with APOE3 much more efficiently than with APOE4 (80% versus 30% inhibition, respectively).

“Also, neurotensin blocked receptor interaction with APOE3 much more efficiently than with APOE4 (80% versus 30% inhibition, respectively) (Fig. 8).”

No accumulation of APOE was seen in mice lacking SORLA or LRP1 in this study.

“In support of our model, no accumulation of APOE was seen in mice lacking SORLA or LRP1 in this study (Fig. 12C–F).”

The levels of other soluble or membrane-tethered APP processing products are not affected by receptor deficiency.

“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).”

Receptor deficiency results in accumulation of Aβ peptides in two AD mouse models.

“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).”

Sortilin plays a role in catabolism of amyloid-β peptides in the brain.

“our data argued for a role of sortilin in catabolism of amyloid-β peptides in the brain.”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

Impaired cellular uptake of APOE is the cause of Aβ accumulation and deposition in the brain of sortilin-deficient mice.

“our data argued for impaired cellular uptake of APOE as the cause of Aβ accumulation and deposition in the brain of sortilin-deficient mice.”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

Sortilin is a major APOE receptor in neurons.

“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.”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

Our findings uncovered APOE-dependent clearance as a molecular mechanism of receptor action in AD.

“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.”

Sortilin deficiency accelerates onset of senile plaque deposition.

“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.”

Sortilin is an essential neuronal pathway for APOE-containing lipoproteins in vivo.

“our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

Our findings have identified a hitherto unknown function for sortilin as neuronal APOE receptor in the brain.

“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.”

Sortilin has a major role as an APOE receptor in neurons.

“So far, our data indicated a major role for sortilin as APOE receptor in neurons.”

Sortilin-deficient animals have functional deficiency in cellular APOE uptake pathways.

“indicating functional deficiency in cellular APOE uptake pathways.”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

There is a link between Aβ catabolism and pro-neurotrophin signaling converging on sortilin.

“suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.”

• AssumptionRests on an assumption: APOE sequesters neurotoxic Aβ peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors.

Co-localization of Aβ40 with cathepsin B suggested predominant lysosomal targeting of internalized peptides.

“Co-localization of Aβ40 with the marker cathepsin B suggested predominant lysosomal targeting of the internalized peptides (Fig.11B).”

Sortilin activity does not impact the rate of Aβ production or clearance in neurons when APOE is absent.

“Thus, sortilin activity does not impact the rate of Aβ production or clearance in neurons when APOE is absent.”

Our studies identified sortilin as another APOE receptor to be considered in this context.

“Now, our studies identified sortilin as another APOE receptor to be considered in this context.”

Sortilin has a direct effect on APOE and Aβ turnover in vivo.

“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.”

Lower (rather than higher) sulfatide levels were observed in another mouse model with neuron-specific LRP1 deficiency previously.

“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).”

• cites Liu et al., 2010 sourceNot checked yet

These observations point towards an isoform-specific interaction of sortilin with human APOE.

“These observations point towards an isoform-specific interaction of sortilin with human APOE.”

Our studies uncovered the relevance of the sortilin receptor pathway in control of lipoprotein homeostasis in the brain.

“Intriguingly, our studies now uncovered the relevance of this receptor pathway in control of lipoprotein homeostasis in the brain as well.”

Many of these data are inconsistent with a simple role for LRP1 in neuronal APOE/Aβ clearance.

“Obviously, many of these data are inconsistent with a simple role for LRP1 in neuronal APOE/Aβ clearance.”

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.

“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.”

Expression of sortilin in the CNS is restricted to neurons.

“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.”

• cites Sarret et al., 2003 sourceNot checked — no full text of the source

Our data substantiate an important role for sortilin in amyloidogenic processes.

“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).”

These data strongly argue for a defect in neuronal clearance of APOE-containing lipoproteins (and associated sulfatides) in mice lacking sortilin.

“These data strongly argue for a defect in neuronal clearance of APOE-containing lipoproteins (and associated sulfatides) in mice lacking this receptor.”

Sortilin represents a pathway where pro-neurotrophin signaling, Aβ catabolism, and brain lipoprotein metabolism converge.

“Thus, this receptor represents a pathway where pro-neurotrophin signaling, Aβ catabolism, and brain lipoprotein metabolism converge.”

Our studies have identified the pro-neurotrophin receptor sortilin as a major neuronal pathway involved in brain APOE and Aβ metabolism.

“In conclusion, our studies have identified the pro-neurotrophin receptor sortilin as a major neuronal pathway involved in brain APOE and Aβ metabolism.”

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.

“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.”

Sortilin-mediated endocytosis likely results in lysosomal degradation of amyloid-β peptides.

“Sortilin-mediated endocytosis likely results in lysosomal degradation of the amyloid-β peptides (Fig. 11B).”