The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index; 4 of the 57 sources its claims cite were checked for support.
Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function
Open accessAbstract
Aims: There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood–brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology; however, their function on neural cells is unknown. Methods and results: The expression of LRP5 and the components and targets of its downstream signalling pathway, the canonical Wnt pathway, including β-catenin, LEF1, VEGF, OPN, MMP7, and ADAM10, is analysed in the brains of Wt and Lrp5−/− mice and in a neuroblastoma cell line. LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells; however, it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5. Conclusions: For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role. In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals. Finally, Lrp5−/− mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In neuronal cells, LRP5 is induced by lipid loading but does not mediate lipid uptake; instead, LDLR handles neuronal lipid internalization, and LRP5 activates canonical Wnt pro-survival signaling. Lrp5−/− mice retain brain LRP5 expression, suggesting brain LRP5 is required for pro-survival processes and embryonic viability.
Key findings
- LRP5 gene expression in Lrp5−/− mouse brain was reduced by 48 ± 2% versus Wt brain, while LRP5 protein was undetectable in all organs except brain; canonical Wnt members and targets were expressed in both Wt and Lrp5−/− brains.
- Neuronal LRP5 expression increased 23.2 ± 2% after 24 h DiI-nLDL, but LRP5 did not colocalize with nLDL and LRP5 silencing did not reduce intracellular cholesteryl esters or DiI-nLDL uptake. LDLR silencing reduced intracellular lipids, whereas LRP1 and CD36 silencing showed no differences.
- nLDL increased β-catenin, LEF1, MMP7, ADAM10, Opn, and VEGF mRNA/protein; LRP5 silencing abrogated β-catenin, LEF1, MMP7, and ADAM10 induction but not Opn or VEGF.
- LRP5 silencing increased apoptosis after H2O2: Bax rose 52 ± 9% in control vs 98 ± 11% in siLRP5; Bcl2 fell 49 ± 3% in control vs 27 ± 1% in siLRP5; early apoptosis rose 52 ± 3% in control vs 91 ± 4% in siLRP5, and late apoptosis rose 36 ± 6% in control vs 654 ± 8% in siLRP5. LRP5 did not appear to play a major role in neuronal autophagy.
Methods
- Wt and Lrp5−/− C57BL/6 mice were fed normal chow for 18 weeks; organs including aorta, heart, liver, spleen, jejunum, and brain were analyzed by PCR, real-time RT-PCR, and Western blot.
- Human SHSY5Y neuroblastoma cells were differentiated with 10 μM retinoic acid for 7 days, silenced for LRP5, LRP1, CD36, or LDLR, and treated with nLDL or DiI-nLDL; analyses included TLC for free/esterified cholesterol, immunofluorescence, Western blot, and flow cytometry for apoptosis after H2O2 or staurosporin.
- Results are expressed as mean ± SEM; comparisons used two-way ANOVA with Bonferroni’s multiple-comparison test, with significance at P < 0.05.
Limitations
- The paper states that high cholesterol-induced functions were studied in cultured neurons and that further analysis in mice brains is needed to determine the role of cholesterol and LRPs in complex biological contexts.
- The paper states that translating putative novel therapies into effective treatment for human patients will be the next challenge.
- Evident from the text: the main functional experiments use an in vitro neuroblastoma cell line and a mouse knockout model, with no direct in vivo measurement of brain cholesterol flux or blood-brain barrier transport.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 57 cited sources checked · 0 supported · 1 flagged · accuracy not yet measured
- Findingown data
There are no differences in cholesterol uptake between CD36-silenced and control cells.
“We then silenced the scavenger receptor CD36 (siCD36) and, similar to LRP1 results, we did not find any differences in cholesterol uptake between the silenced and the control cells (Figure 4C and D).”
Quote in the paperSubstantial claim - Findingown data
LRP5 protein expression in Lrp5-/- mice is undetectable in all organs except for the brain, where a faint band of similar molecular weight to that observed in Wt mice was detected.
“Again, LRP5 protein expression in Lrp5 -/-mice is undetectable in all the organs except for the brain, where a faint band of a similar molecular weight than that observed in Wt mice was detected (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Silencing LDLR reduces lipid uptake in neuronal cells.
“found a reduced lipid uptake in siLDLR-neuronal cells”
Quote in the paperSubstantial claim - Findingown data
A strong LRP5 staining was observed after 24 h DiI-nLDL treatment.
“A strong LRP5 staining was observed after 24 h DiI-nLDL (200 μg/mL nLDL) treatment confirming RNA and Western Blot (WB) analyses.”
Quote in the paperNot a substantial claim - Findingown data
Neurons without LRP1 show no reduction in intracellular lipid accumulation.
“no intracellular lipid accumulation reduction was observed in neurons without LRP1”
Quote in the paperSubstantial claim
- Findingown data
LRP5 does not play a major role in lipid uptake in neurons.
“LRP5 does not play a major role in lipid uptake in neurons.”
Quote in the paperSubstantial claim - Findingown data
There was a significant increase in the Bax/Bcl2 ratio of LRP5-silenced and H2O2-treated cells compared with control cells.
“Therefore, there was a significant increase in the Bax/Bcl2 ratio of LRP5-silenced and H 2 O 2 -treated cells compared with control cells, indicating increased cell death in cells without LRP5 (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
H2O2 treatment caused a 49 ± 3% reduced expression of the anti-apoptotic gene Bcl2 in control cells.
“We also determined the levels of expression of the anti-apoptotic gene Bcl2 and found a 49 ± 3% reduced expression after H 2 O 2 treatments in control cells, while in cells without LRP5, this decrease was of 27 ± 1%.”
Quote in the paperSubstantial claim - Findingown data
The highest DiI-nLDL staining intensity was observed at 24 h.
“The highest staining intensity was observed at 24 h (Figure 2B).”
Quote in the paperNot a substantial claim - Findingown data
Cells without LRP5 express more active Caspase 3 than control cells.
“The analyses of the intracellular pro-apoptotic protein Caspase 3 showed that cells without LRP5 express more active Caspase 3 than control cells, supporting the anti-apoptotic role of LRP5 (Figure 6D).”
Quote in the paperSubstantial claim - Findingown data
Twenty-four hours after nLDL treatment, both mRNA and protein levels of β-catenin and LEF1 increased.
“Twenty-four hours after nLDL treatment, both mRNA and protein levels of the structural canonical Wnt proteins β-catenin and LEF1 increased.”
Quote in the paperSubstantial claim - Findingown data
The expression of canonical Wnt pathway members β-catenin and LEF1 and targets VEGF, Opn, MMP7, and ADAM10 was observed in the brain samples of both Wt and Lrp5-/- mice.
“The expression of canonical Wnt pathway members (β-catenin and LEF1) and targets (VEGF, Opn, MMP7, and ADAM10) was observed in the brain samples of both Wt and Lrp5 -/-mice, indicating the pathway viability in the brains of Lrp5 -/-mice (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
In cells without LRP5, the H2O2-induced increase in Bax was 98 ± 11%.
“In cells without LRP5, this increase was of 98 ± 11%.”
Quote in the paperSubstantial claim - Findingown data
Neuronal LRP5 expression is increased after lipid exposure.
“although there is an increased expression of neuronal LRP5 after lipid exposure”
Quote in the paperNot a substantial claim - Findingown data
LDLR-silenced cells contain less intracellular lipids than their controls.
“Finally, we performed the same experiment in LDLR-silenced neuronal cells (siLDLR), and the results show that LDLR-silenced cells contain less intracellular lipids than their controls, suggesting that the classic LDLR is in charge of lipid uptake in neuronal cells (Figure 4E and F).”
Quote in the paperSubstantial claim - Findingown data
LRP5 is expressed at low but significant levels in the brain of Lrp5 -/- mice.
“we first show there is a low, but significant expression of LRP5 in the brain of Lrp5 -/-mice.”
Quote in the paperSubstantial claim - Findingown data
LRP5 gene expression in Lrp5-/- mice brains showed a 48 ± 2% reduction compared with Wt mice brains.
“LRP5 gene expression in Lrp5 -/-mice brains showed a 48 ± 2% reduction in that observed in Wt mice brains (Figure 1A).”
Quote in the paperNot a substantial claim - Findingown data
Lrp5-/- mice showed the absence of LRP5 gene transcription in all organs except for the brain.
“Lrp5 -/-mice showed the absence of LRP5 gene transcription in all organs except for the brain.”
- Also stated in: § Abstract · plain
“Lrp5 -/-mice have maintained expression of LRP5 only in the brain”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Neurons can accumulate intracellular lipids.
“For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role.”
Quote in the paperSubstantial claim - Findingown data
LDL-induced expression of MMP7 and ADAM10 was abrogated in si-LRP5 cells.
“Similar results are observed for MMP7 and ADAM10.”
Quote in the paperSubstantial claim - Findingown data
STP treatments show increased early and late apoptosis in cells without LRP5.
“Similar to the results of H 2 O 2 treatments, the results of STP treatments show increased early and late apoptosis in cells without LRP5 (Figure 6E), while no differences in LRP5-silenced cells in respect to control cells were observed after cellular necrosis staining (Figure 6F).”
Quote in the paperSubstantial claim - Findingown data
No differences in LRP5-silenced cells with respect to control cells were observed after cellular necrosis staining.
“Similar to the results of H 2 O 2 treatments, the results of STP treatments show increased early and late apoptosis in cells without LRP5 (Figure 6E), while no differences in LRP5-silenced cells in respect to control cells were observed after cellular necrosis staining (Figure 6F).”
Quote in the paperSubstantial claim - Findingown data
LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells.
“LRP5 expression is increased in a time-and dose-dependent manner after lipid loading in neuronal cells;”
Quote in the paperNot a substantial claim - Findingown data
DiI-nLDL intracellular accumulation occurred in a concentration-dependent manner.
“TLC analyses showed DiI-nLDL intracellular accumulation in a concentration-dependent manner (Figure 2C and D).”
Quote in the paperNot a substantial claim - Findingown data
There are no variations in cholesteryl ester intracellular accumulation between control and LRP1-silenced cells.
“We transfected the cells with siRNA-LRP1, treated them with lipids, and analysed the cholesteryl ester intracellular accumulation and did not find any variations between control and LRP1-silenced cells, indicating that LRP1 is not responsible for lipid uptake in these cells either (Figure 4A and B).”
Quote in the paperSubstantial claim - Findingown data
LDL-induced expression of β-catenin and LEF1 was abrogated in si-LRP5 cells.
“Interestingly, LDL-induced expression of β-catenin and LEF1 was abrogated in si-LRP5 cells.”
Quote in the paperSubstantial claim - Findingown data
LRP5 was highly transcribed in the aorta, heart, and liver of Wt mice.
“Interestingly, LRP5 was highly transcribed in the aorta, heart, and liver of Wt mice.”
Quote in the paperNot a substantial claim - Findingown data
Lipid uptake downregulation is not observed in LRP5-silenced cells.
“Lipid uptake downregulation is not observed in LRP5-silenced cells, confirming that LRP5 is not involved in lipid uptake in neurons (Figure 3C).”
Quote in the paperSubstantial claim - Findingnone given
Lrp5 -/- mice do not show LRP5 expression in any other organ.
“Lrp5 -/-mice do not show LRP5 expression in any other organ.”
Quote in the paperSubstantial claim - Findingown data
Treatment of neurons with lipids showed a time- and dose-dependent lipid uptake.
“Treatment of neurons with lipids showed a time-and dosedependent lipid uptake”
Quote in the paperNot a substantial claim - Findingown data
After nLDL incubation, neuronal cells show increased gene and protein levels of LRP5, β-catenin, LEF1, Opn, VEGF, MMP7, and ADAM10.
“After nLDL incubation, the neuronal cells showed increased gene and protein levels of Wnt pathway proteins and targets, including LRP5, β-catenin, LEF1, Opn, VEGF, MMP7, and ADAM10”
Quote in the paperSubstantial claim - Findingown data
H2O2 treatment caused a 52 ± 9% increase in the expression levels of the pro-apoptotic protein Bax in control cells.
“The results show a 52 ± 9% increase in the expression levels of the pro-apoptotic protein Bax after H 2 O 2 treatments in control cells (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
No colocalization between LRP5 and nLDL was observed.
“However, no colocalization between LRP5 and nLDL was observed, suggesting that LRP5 is not involved in neuronal SHSY5Y lipid uptake (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
In cells without LRP5, the H2O2-induced decrease in Bcl2 was 27 ± 1%.
“We also determined the levels of expression of the anti-apoptotic gene Bcl2 and found a 49 ± 3% reduced expression after H 2 O 2 treatments in control cells, while in cells without LRP5, this decrease was of 27 ± 1%.”
Quote in the paperSubstantial claim - Findingown data
Both p62 and LC3B are down-regulated in control conditions when autophagy is promoted by H2O2 or STP treatments.
“The results show that both p62 and LC3B are down-regulated in control conditions when autophagy is promoted by H 2 O 2 treatments (Figure 6H) or by STP treatments (Figure 6I).”
Quote in the paperNot a substantial claim - Findingown data
Cells without LRP5 expressed more active Caspase 3 than control cells after STP treatment.
“An anti-apoptotic role for LRP5 was further supported by Caspase 3 western blotting, where cells without LRP5 expressed more active Caspase 3 than control cells (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
LRP5 protein expression is readily detected in the aorta, heart, liver, spleen, jejunum, and brain of Wt mice.
“In a similar way, LRP5 protein expression is readily detected in the aorta, heart, liver, spleen, jejunum, and brain of Wt mice.”
Quote in the paperNot a substantial claim - Findingown data
There were no significant differences between LRP5-silenced and control cells after H2O2 or STP treatments.
“However, there were no significant differences between LRP5-silenced and control cells after H 2 O 2 or STP treatments, suggesting that LRP5 does not play a major role in cellular autophagic processes in neuronal cells (Figure 6H and I).”
Quote in the paperSubstantial claim - Findingown data
The LRP5 expression increase at 24 h of DiI-nLDL incubation was not concentration dependent.
“LRP5 expression analyses showed a mild 23.2 ± 2% increase in LRP5 expression at 24 h of DiI-nLDL incubation (Figure 2E), which was not concentration dependent (Figure 2F).”
Quote in the paperNot a substantial claim - Findingown data
CD36 is not accountable for neuronal lipid uptake.
“The same was true for CD36.”
Quote in the paperSubstantial claim - Findingown data
There is no reduction in intracellular DiI staining in LRP5-silenced neuronal cells compared with control cells.
“The results do not show a reduction in intracellular DiI staining in LRP5-silenced neuronal cells compared with control cells (Figure 3E and F), further supporting our previous results.”
Quote in the paperSubstantial claim - Findingown data
All Lrp5 -/- mice showed LRP5 expression in the brain.
“all Lrp5 -/-mice showed LRP5 expression in brain”
Quote in the paperSubstantial claim - Findingown data
siRNA-LRP5 SHSY5Y cells after H2O2 treatments showed similar PI staining to control cells.
“However, siRNA-LRP5 SHSY5Y cells after H 2 O 2 treatments showed similar PI staining than control cells, suggesting that LRP5 does not participate in the necrotic process (Figure 6C).”
Quote in the paperSubstantial claim - Findingown data
LRP5 expression showed a mild 23.2 ± 2% increase at 24 h of DiI-nLDL incubation.
“LRP5 expression analyses showed a mild 23.2 ± 2% increase in LRP5 expression at 24 h of DiI-nLDL incubation (Figure 2E), which was not concentration dependent (Figure 2F).”
Quote in the paperNot a substantial claim - Findingown data
Early and late apoptosis is increased in H2O2- and STP-treated cells devoid of LRP5.
“early and late apoptosis was increased in both H 2 O 2 and STP-treated cells devoid of LRP5.”
Quote in the paperSubstantial claim - Findingown data
LRP5 expression reduces apoptosis.
“LRP5 expression reduces apoptosis.”
Quote in the paperSubstantial claim - Findingown data
LRP5 does not play a major role in the autophagic processes of neuronal cells.
“LRP5 does not seem to play a major role in the autophagic processes of neuronal cells.”
Quote in the paperNot a substantial claim - Findingown data
Lrp5 -/- mice maintain LRP5 expression only in the brain.
“mice knock-out for LRP5 has maintained the expression of LRP5 only in the brain”
Quote in the paperSubstantial claim - Findingown data
LRP5 does not colocalize with nLDL in differentiated neurons.
“LRP5 does not colocalize with nLDL in differentiated neurons.”
Quote in the paperSubstantial claim - Findingown data
Neuronal cells take up lipids by LDLR.
“Neuronal cell uptake lipids by LDLR.”
Quote in the paperSubstantial claim - Findingown data
Cells without LRP5 show high levels of activated Caspase 3.
“the analyses of intracellular levels of Caspase 3 in neuronal cells also showed high levels of the activated form in cells without LRP5”
Quote in the paperSubstantial claim - Premisecitation
During the progression of Alzheimer's disease, the β-amyloid protein can bind to the Frizzled receptor inhibiting downstream phosphorylation and preventing canonical Wnt signalling induction.
“During the progression of Alzheimer's disease, the β-amyloid protein can bind to the Frizzled receptor inhibiting downstream phosphorylation and preventing canonical Wnt signalling induction.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Magdesian, 2008, Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling, J Biol Chem source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation
Aortas from Lrp5-/- mice show less lipid content than those from Wt mice.
“Furthermore, aortas from Lrp5 -/-mice show less lipid content than those from Wt mice 27,28”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Borrell-Pages, 2014, Cholesterol modulates LRP5 expression in the vessel wall, Atherosclerosis source
Checked before — its earlier verdict is held back until a new check runs.
- cites [28] Borrell-Pagès, 2015, LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice, J Cell Mol Med source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation
Blood-circulating LDL molecules can cross the blood-brain barrier in a process mediated by the LDLR expressed in caveolin- or clathrin-coated vesicles in specialized BBB-endothelial cells.
“Blood-circulating LDL molecules can also cross the BBB in a process mediated by the LDLR expressed in caveolin-or clathrin-coated vesicles in specialized BBB-endothelial cells.22”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Dehouck, 1997, A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier, J Cell Biol source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation
Macrophages that do not express LRP5 show less intracellular cholesterol ester accumulation than Wt macrophages.
“Also, macrophages that do not express LRP5 show less intracellular cholesterol ester accumulation than Wt macrophages.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Borrell-Pagès, 2011, Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages, Eur Heart J source
- Premisecitation
In the mammalian central nervous system, dysregulation of the Wnt pathway inhibits timely myelination and remyelination of neurons.
“In the mammalian central nervous system, dysregulation of the Wnt pathway inhibits timely myelination and remyelination of neurons, 14”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Fancy, 2009, Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS, Genes Dev source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
The canonical Wnt pathway has to be finely regulated to avoid brain diseases.
“Taken together, these results show that the canonical Wnt pathway has to be finely regulated to avoid brain diseases.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 does not participate in the necrotic process.
“However, siRNA-LRP5 SHSY5Y cells after H 2 O 2 treatments showed similar PI staining than control cells, suggesting that LRP5 does not participate in the necrotic process (Figure 6C).”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 has an anti-apoptotic role in neurons.
“siRNA-LRP5 H 2 O 2 -treated cells showed a 91 ± 4% increase in early apoptosis and a 654 ± 8% increase in late apoptosis when compared with control cells (untreated siR SHSY5Y cells), indicating an anti-apoptotic role for LRP5 (Figure 6B).”
- Also stated in: § 4. Discussion · plain
“further supporting an anti-apoptotic role of LRP5 in neurons.”
Quote in the paperSubstantial claim - Also stated in: § 4. Discussion · plain
- Interpretationown data
The classic LDLR is in charge of lipid uptake in neuronal cells.
“Finally, we performed the same experiment in LDLR-silenced neuronal cells (siLDLR), and the results show that LDLR-silenced cells contain less intracellular lipids than their controls, suggesting that the classic LDLR is in charge of lipid uptake in neuronal cells (Figure 4E and F).”
Quote in the paperSubstantial claim - Interpretationreasoning
The need of brain LRP5 to elicit pro-survival processes and embryonic viability is biologically plausible.
“Lrp5 -/-mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 does not play a major role in cellular autophagic processes in neuronal cells.
“However, there were no significant differences between LRP5-silenced and control cells after H 2 O 2 or STP treatments, suggesting that LRP5 does not play a major role in cellular autophagic processes in neuronal cells (Figure 6H and I).”
Quote in the paperSubstantial claim - Interpretationown data
Wnt pathway activation is induced after lipid loading in neuronal cells.
“indicating that Wnt pathway activation is induced after lipid loading.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 silencing increases cell death in H2O2-treated neuronal cells.
“Therefore, there was a significant increase in the Bax/Bcl2 ratio of LRP5-silenced and H 2 O 2 -treated cells compared with control cells, indicating increased cell death in cells without LRP5 (Figure 6A).”
Quote in the paperSubstantial claim - Interpretationown data
LRP1 is not responsible for lipid uptake in neuronal SHSY5Y cells.
“We transfected the cells with siRNA-LRP1, treated them with lipids, and analysed the cholesteryl ester intracellular accumulation and did not find any variations between control and LRP1-silenced cells, indicating that LRP1 is not responsible for lipid uptake in these cells either (Figure 4A and B).”
Quote in the paperSubstantial claim - Interpretationown data
A complete absence of LRP5 in the brain is incompatible with life.
“suggesting that a complete absence of LRP5 in the brain is incompatible with life.”
Quote in the paperSubstantial claim - Interpretationown data
CD36 is not responsible for lipid uptake in neuronal SHSY5Y cells.
“We then silenced the scavenger receptor CD36 (siCD36) and, similar to LRP1 results, we did not find any differences in cholesterol uptake between the silenced and the control cells (Figure 4C and D).”
Quote in the paperSubstantial claim - Interpretationown data
LDLR is the receptor involved in lipid uptake in neuronal cells.
“indicating that the LDLR is the receptor involved in lipid uptake in neuronal cells.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals.
“In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals.”
Quote in the paperSubstantial claim - Interpretationown data
LRP1 is not accountable for neuronal lipid uptake.
“indicating that LRP1 is not accountable for neuronal lipid uptake.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 does not participate in cholesterol homeostasis in neuronal cells.
“it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses.”
Quote in the paperSubstantial claim - Interpretationown data
The canonical Wnt pathway is viable in the brains of Lrp5-/- mice.
“The expression of canonical Wnt pathway members (β-catenin and LEF1) and targets (VEGF, Opn, MMP7, and ADAM10) was observed in the brain samples of both Wt and Lrp5 -/-mice, indicating the pathway viability in the brains of Lrp5 -/-mice (Figure 1C).”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 is not involved in lipid uptake in neurons.
“Lipid uptake downregulation is not observed in LRP5-silenced cells, confirming that LRP5 is not involved in lipid uptake in neurons (Figure 3C).”
Quote in the paperSubstantial claim - Interpretationown data
Neurons can accumulate small amounts of intracellular lipids.
“indicating that neurons can accumulate small amounts of intracellular lipids.”
Quote in the paperNot a substantial claim - Interpretationown data
LRP5 is not involved in neuronal SHSY5Y lipid uptake.
“However, no colocalization between LRP5 and nLDL was observed, suggesting that LRP5 is not involved in neuronal SHSY5Y lipid uptake (Figure 3A).”
Quote in the paperSubstantial claim - Interpretationown data
Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5.
“Neurons challenged with staurosporin and H 2 O 2 display an anti-apoptotic protective role for LRP5.”
Quote in the paperSubstantial claim - Interpretationown data
Lipid uptake in neurons is performed mainly by the LDLR.
“For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 is involved in survival processes in neurons.
“Here, we show the involvement of LRP5 in survival processes in neurons.”
Quote in the paperSubstantial claim - Interpretationown data
LRP5 has an antiapoptotic function in the H2O2-induced apoptotic pathway.
“suggesting that LRP5 is involved in the H 2 O 2 -induced apoptotic pathway with an antiapoptotic function.”
Quote in the paperSubstantial claim - Interpretationown data
In neurons, nLDL triggers the Wnt pathway only in the presence of LRP5 to induce the transcription of proteins that will develop pro-survival mechanisms.
“these results suggest that in neurons, nLDL triggers the Wnt pathway only in the presence of LRP5 to induce the transcription of proteins that will develop pro-survival mechanisms.”
Quote in the paperSubstantial claim - Premisecitation
MMP7 expression is greatly increased after injury in rat sciatic nerves.
“its expression is greatly increased after injury in rat sciatic nerves.58”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Qin, 2016, Differential temporal expression of matrix metalloproteinases following sciatic nerve crush, Neural Regen Res source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationreasoning
ADAM10 and MMP7 are regulators of protective functions in the brain.
“Taken together, these results point to ADAM10 and MMP7 as regulators of protective functions in the brain.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 38
- It may state two separate claims as one. 30
- The quote only partly states this claim. 1
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOPN expression is increased after NFκB pathway activation.
“OPN expression is increased after NFκB pathway activation 48”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] Kariya, 2022, Osteopontin in cancer: mechanisms and therapeutic targets, Int J Transl Med source
Section 5, “OPN in Tumor Progression” (page unavailable), describes the opposite direction: OPN binding activates NF-κB signaling. Section 8 likewise places NF-κB signaling downstream of OPN induction, not as the trigger for increased OPN expression. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationLRP1 belongs to the same family as LRP5 and is known to regulate crucial processes that help maintain synaptic integrity and cholesterol homeostasis in the brain.
“LRP1 belongs to the same family as LRP5 and is known to regulate crucial processes that help maintain synaptic integrity and cholesterol homeostasis in the brain.[44][45][46]”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [44] Liu, 2010, Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration, J Neurosci source
The Results report that LRP1 knockdown reduced neuronal cholesterol and markers of synaptic integrity, and the Discussion describes LRP1's role in brain lipid metabolism and synapse integrity. The Introduction places LRP1 in the low-density lipoprotein receptor family, but our copy does not mention LRP5, so it does not establish the stated family relationship with LRP5. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [45] Herz, 2001, LRP: a multifunctional scavenger and signaling receptor, J Clin Invest source
The Introduction places LRP in the LDL receptor gene family, and “Emerging functions in neurotransmission” describes its possible role in synaptic plasticity. But the paper does not identify LRP5 as a family member, and “Lipoprotein metabolism” presents LRP-mediated uptake of cholesterol in the brain as a possibility, not an established role in cholesterol homeostasis. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [46] Lillis, 2008, LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies, Physiol Rev source
Section II (Structural organization of LRP1; page unavailable) identifies LRP1 and LRP5 as members of the LDL receptor family. Section IX.F (Role of LRP1 in neurons, Summary; page unavailable) says a role in brain synaptic transmission is possible but not established. The paper discusses cholesterol-rich lipoprotein clearance in the liver (Section V.D), not LRP1 maintaining cholesterol homeostasis in the brain; it also does not establish that LRP1 maintains synaptic integrity. (LLM, conf=0.88)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataIn the absence of LRP5, the nLDL-induced increase in β-catenin, LEF1, MMP7, and ADAM10 is greatly reduced, while OPN and VEGF remain induced.
“the increased expression of these Wnt proteins and targets was greatly reduced in the absence of LRP5 only in Wnt structural proteins (β-catenin and LEF1) and in some Wnt targets (MMP7 and ADAM10), while other indirect Wnt targets (OPN and VEGF) are induced”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIntracellular DiI-nLDL depositions were observed immediately upon 2 h of treatment and lasted for 48 h.
“The results show intracellular DiI-nLDL depositions immediately upon 2 h of treatment and these lasted for 48 h.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe absence of LRP5 does not reduce neuronal intracellular cholesteryl esters nor intracellular lipids.
“The absence of LRP5 does not reduce neuronal intracellular cholesteryl esters nor intracellular lipids.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTwenty-four hours after H2O2 treatments, there was a 52 ± 3% increase in early apoptosis and a 36 ± 6% increase in late apoptosis in the control cells.
“Twentyfour hours after H 2 O 2 treatments, there was a 52 ± 3% increase in early apoptosis (AnnV + cells) and a 36 ± 6% increase in late apoptosis in the control cells (AnnV + /PI + cells; Figure 6B).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataDifferent proteins and target genes of the canonical Wnt pathway are expressed in the brains of wild-type and Lrp5 -/- mice.
“we analysed the expression of different proteins and target genes of the pathway and found that they were all expressed”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOpn and VEGF were not affected by LRP5 silencing.
“In contrast, Opn and VEGF were not affected by LRP5 silencing.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown datasiRNA-LRP5 H2O2-treated cells showed a 91 ± 4% increase in early apoptosis and a 654 ± 8% increase in late apoptosis when compared with control untreated siR SHSY5Y cells.
“siRNA-LRP5 H 2 O 2 -treated cells showed a 91 ± 4% increase in early apoptosis and a 654 ± 8% increase in late apoptosis when compared with control cells (untreated siR SHSY5Y cells), indicating an anti-apoptotic role for LRP5 (Figure 6B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCells without LRP5 express higher levels of Bax and lower levels of Bcl2 than control cells.
“Cells without LRP5 expressed higher levels of Bax and lower levels of Bcl2 than control cells”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenAnimal procedures conform to the guidelines from Directive 2010/63/EU and the Position of the American Heart Association on Research Animals use.
“All animal procedures conform to the guidelines from Directive 2010/63/EU of the European Parliament and the 'Position of the American Heart Association on Research Animals use' (11 November 1984).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCholesterol in the central nervous system is mainly synthesized by astrocytes.
“Cholesterol in the central nervous system is mainly synthesized by astrocytes.20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Nieweg, 2009, Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats, J Neurochem source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the adult, LRPs are involved in the clearance of cholesterol and cholesteryl ester-containing LDL particles from the blood.
“In the adult, LRPs are involved for their role in the clearance of cholesterol and cholesteryl ester-containing LDL particles from the blood.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Borrell-Pagès, 2011, Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages, Eur Heart J source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe canonical Wnt signalling pathway participates in the formation of the antero-posterior axis patterning in axonal pathfinding and in synaptogenesis.
“The canonical Wnt signalling pathway participates in the formation of the antero-posterior axis patterning in axonal pathfinding and in synaptogenesis.[11][12][13]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] Yamaguchi, 2001, Heads or tails: Wnts and anterior–posterior patterning, Curr Biol source
- cites [12] Ciani, 2005, WNTs in the vertebrate nervous system: from patterning to neuronal connectivity, Nat Rev Neurosci source
- cites [13] Salinas, 2008, Wnt signaling in neural circuit assembly, Annu Rev Neurosci source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFluorescence was measured blindly by two independent investigators.
“Fluorescence was measured from individual stacks; the number of pixels and the mean per field of view were measured blindly by two independent investigators.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDkk-1, a canonical Wnt inhibitor, is released into the circulation after the occurrence of cerebral ischaemia events.
“Dkk-1, a canonical Wnt inhibitor, is released into the circulation after the occurrence of cerebral ischaemia events.15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Seifert-Held, 2011, Circulating Dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease, Atherosclerosis source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIncreased LRP5 expression is induced by extracellular lipids in primary cultures of human monocytes and macrophages and human vascular smooth muscle cells and in vivo in ApoE-/- mice.
“Increased LRP5 expression is induced by extracellular lipids in the primary cultures of human monocytes and macrophages and human vascular smooth muscle cells 3 and in vivo in ApoE -/-mice.26”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Borrell-Pagès, 2011, Wnt pathway activation, cell migration, and lipid uptake is regulated by low-density lipoprotein receptor-related protein 5 in human macrophages, Eur Heart J source
- cites [26] Fujino, 2003, Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion, Proc Natl Acad Sci U S A source
It may state two separate claims as one.
PremisecitationDisruption of BBB integrity can lead to an increased permeability of the endothelium for cholesterol-carrying lipoproteins and facilitate the exposure of blood-circulating components to neurons.
“In addition, disruption of BBB integrity can lead to an increased permeability of the endothelium for cholesterol-carrying lipoproteins and facilitate the exposure of bloodcirculating components to neurons.[23][24][25]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [23] Finch, 1993, TGF-beta 1 is an organizer of responses to neurodegeneration, J Cell Biochem source
Checked before — its earlier verdict is held back until a new check runs.
- cites [24] Lin, 2010, Resveratrol protects against oxidized LDL-induced breakage of the blood-brain barrier by lessening disruption of tight junctions and apoptotic insults to mouse cerebrovascular endothelial cells, J Nutr source
Checked before — its earlier verdict is held back until a new check runs.
- cites [25] Acharya, 2013, Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib, J Alzheimers Dis source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTranscytosis across the blood-brain barrier occurs as an efflux mechanism to eliminate cholesterol excess.
“Transcytosis across the blood-brain barrier (BBB) occurs as an efflux mechanism to eliminate cholesterol excess.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Pifferi, 2021, Lipid transport and metabolism at the blood-brain interface: implications in health and disease, Front Physiol source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe presence of LRP5 alleles was assessed by PCR amplification from DNA extracted from tail biopsies.
“The presence of LRP5 alleles was assessed by polymerase chain reaction (PCR) amplification from DNA extracted from tail biopsies in wild-type, heterozygous, and homozygous littermates.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Premisecitationβ-Amyloid can also increase the activity of the Wnt pathway inhibitor GSK3β, inducing neuronal apoptosis and increasing the neurotoxicity associated with β-amyloid.
“β-Amyloid can also increase the activity of the Wnt pathway inhibitor GSK3β, inducing neuronal apoptosis and increasing the neurotoxicity associated with β-amyloid.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Farías, 2004, M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity. A role for Wnt signaling pathway, Neurobiol Dis source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenTransfection efficiency was analysed by LRP5 RNA expression by real-time RT-PCR and normalized to r18S RNA expression.
“Transfection efficiency was analysed by LRP5 RNA expression by real-time RT-PCR and normalized to r18S RNA expression.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAtherosclerosis is 6-to 19-fold greater in extracranial arteries than in intracranial arteries, mostly due to the anti-oxidant enzymes present in brain arteries that provide resistance to atherosclerosis lesion development.
“Early studies addressing the topic of cholesterol content in human brain arteries show that atherosclerosis is 6-to 19-fold greater in extracranial arteries than in intracranial arteries, mostly due to the anti-oxidant enzymes present in brain arteries that provide resistance to atherosclerosis lesion development.18”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] D’Armiento, 2001, Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis, Stroke source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductreasoningThe authors used the minimum number of animals required to achieve statistical significance.
“We are committed to the '3Rs' principle and hence used the minimum number of animals required to achieve statistical significance.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataControls without primary antibodies showed no fluorescence labelling.
“Controls without primary antibodies showed no fluorescence labelling.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenRNA purity was checked by A260/A280 ratio, with ratios between 1.8 and 2.1 considered acceptable.
“The concentration was determined by using a NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies, Inc., Wilmington, DE, USA), and purity was checked by using the A260/ A280 ratio (ratios between 1.8 and 2.1 were considered acceptable).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThis binding induces transcription of canonical Wnt direct and indirect target genes, including c-jun, cyclin D1, VEGF, MMP7, ADAM10, and Opn.
“This binding induces the transcription of canonical Wnt direct and indirect target genes, including c-jun, 4 cyclin D1, 5 VEGF, 6 MMP7, 7 ADAM 10, 8 and Opn. 9”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Mann, 1999, Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas, Proc Natl Acad Sci U S A source
Checked before — its earlier verdict is held back until a new check runs.
- cites [5] Shtutman, 1999, The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway, Proc Natl Acad Sci U S A source
- cites [6] Qu, 2014, Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma, Oncol Lett source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the absence of other atherogenic risk factors, hypercholesterolaemia during foetal development induces an extensive formation of fatty streaks in extracranial arteries but not in intracranial arteries.
“Furthermore, a comparison of intracranial vs. extracranial fatty streak formation of human foetuses from normocholesterolaemic and hypercholesterolaemic mothers shows that, in the absence of other atherogenic risk factors, hypercholesterolaemia during foetal development induces an extensive formation of fatty streaks in extracranial arteries but not in intracranial arteries.19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Napoli, 1999, Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries, Circulation source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe siR control did not exert any effect on LRP5 expression.
“siR was used as a control and did not exert any effect on LRP5 expression.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA role for both LRP5 and LRP6 has been described in the cerebellum where deletion of both LRP5 and LRP6 together, but not individually, resulted in defective foliation and lamination of the cerebellum during post-natal development.
“A role for both LRP5 and LRP6 has been described in the cerebellum where the deletion of both LRP5 and LRP6 together, but not individually, resulted in defective foliation and lamination of the cerebellum during post-natal development.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Huang, 2016, Lrp5/6 are required for cerebellar development and for suppressing TH expression in Purkinje cells via β-catenin, Mol Brain source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationLRP5 gene and protein levels are upregulated in the hearts of hypercholesterolaemic mice and in hypercholesterolaemic ischaemic human hearts.
“and LRP5 gene and protein levels are also upregulated in the hearts of hypercholesterolaemic mice and in hypercholesterolaemic ischaemic human hearts.29,30”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] Borrell-Pages, 2016, LRP5/canonical Wnt signalling and healing of ischemic myocardium, Basic Res Cardiol source
- cites [30] Badimon, 2019, GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage, PLoS One source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenWestern blot normalization was performed against β-actin.
“Normalization was performed against β-actin.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe canonical Wnt signalling pathway is mainly involved in cell proliferation and survival in vital biological processes, including organogenesis and embryogenesis.
“The canonical Wnt signalling pathway is mainly involved in cell proliferation and survival in vital biological processes, including organogenesis and embryogenesis.1,2”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Mao, 2001, Low-density lipoprotein receptor-related protein-5 binds to axin and regulates the canonical Wnt signaling pathway, Mol Cell source
Checked before — its earlier verdict is held back until a new check runs.
- cites [2] Johnson, 2004, The high bone mass family—the role of Wnt/Lrp5 signaling in the regulation of bone mass, J Musculoskel Neuron Interact
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenThe study protocols for mice were approved by the institutional Animal Care and Use Committee and authorized by the local government commission.
“The study protocols for mice were approved by the institutional Animal Care and Use Committee (ICCC051/5422) and authorized by the local government commission.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationADAM10 has key roles in neural development, axonal growth, and myelination.
“ADAM10 has key roles in neural development, 52 is involved in axonal growth and myelination, 52”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Yang, 2006, The ADAMs family: coordinators of nervous system development, plasticity and repair, Prog Neurobiol source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationFollowing an acute ischaemic stroke, the PKC pathway in endothelial cells is activated and the expression of VEGF and HIF1α is enhanced.
“following an acute ischaemic stroke, the PKC pathway in endothelial cells is activated and the expression of VEGF and HIF1α is enhanced.51”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Moon, 2021, Repair mechanisms of the neurovascular unit after ischemic stroke with a focus on VEGF, Int J Mol Sci source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataCD36, LRP1, and LRP5 do not play a major role in neuronal lipid uptake.
“For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSeveral brain disorders including Alzheimer's disease, Huntington's disease, and Parkinson's disease run with defects in brain cholesterol metabolism.
“Several brain disorders including Alzheimer's disease, Huntington's disease, and Parkinson's disease run with defects in brain cholesterol metabolism.[39][40][41]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [39] Block, 2010, Altered cholesterol and fatty acid metabolism in Huntington disease, J Clin Lipidol source
- cites [40] Di Paolo, 2011, Linking lipids to Alzheimer’s disease: cholesterol and beyond, Nat Rev Neurosci source
- cites [41] Wang, 2011, Statins: multiple neuroprotective mechanisms in neurodegenerative diseases, Exp Neurol source
It may state two separate claims as one.
Interpretationown dataIn neurons, LDL triggers the activation of the canonical Wnt pathway with different activations of target gene expression depending on LRP5.
“These results indicate that in neurons, LDL triggers the activation of the canonical Wnt pathway with different activations of target gene expression depending on LRP5 (Figure 5A-D).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA role for LRP5 has been described in the formation of the cerebellum.
“A role for LRP5 has been described in the formation of the cerebellum.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Huang, 2016, Lrp5/6 are required for cerebellar development and for suppressing TH expression in Purkinje cells via β-catenin, Mol Brain source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCholesterol de novo synthesis is higher in astrocytes than in neuronal cells in post-natal rats.
“Cholesterol de novo synthesis is higher in astrocytes than in neuronal cells in post-natal rats.20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Nieweg, 2009, Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats, J Neurochem source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOPN influences PI3K/AKT/mTOR signalling to regulate migration, phagocytosis, and the expression of inflammatory factors in microglia.
“is known to influence PI3K/AKT/mTOR signalling 49 to regulate migration, phagocytosis, and the expression of inflammatory factors in microglia.50”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [49] Ahmed, 2010, Osteopontin selectively regulates p70S6K/mTOR phosphorylation leading to NF-κB dependent AP-1-mediated ICAM-1 expression in breast cancer cells, Mol Cancer source
Checked before — its earlier verdict is held back until a new check runs.
- cites [50] Yu, 2017, The effect of osteopontin on microglia, Biomed Res Int source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataThe canonical Wnt pathway is functional and can be activated in both wild-type and Lrp5 -/- mice.
“indicating that the pathway is functional and can be activated in both wild-type and Lrp5 -/-mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationCholesterol is needed for brain survival during development and in adult life, and the amount of cholesterol in the brain has to be accurately maintained for correct brain function.
“Cholesterol is needed for brain survival during development, and in the adult life, and for a correct brain function, the amount of cholesterol in the brain has to be accurately maintained. [36][37]7][38]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36][37]7][38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLDLR plays a major role in the regulation of liver lipid homeostasis.
“LDLR, a receptor that plays a major role in the regulation of liver lipid homeostasis, 47”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Go, 2012, Low-density lipoprotein receptor (LdLr) family orchestrates cholesterol homeostasis, Yale J Biol Med
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFor each cytotoxicity sample, at least 10,000 events were acquired.
“For each sample, at least 10 000 events were acquired on a MACSQuant Analyzer 10 (Miltenyi Biotec, Bergisch Gladbach, Germany).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningADAM10 and MMP7 seem to be under canonical Wnt pathway regulation.
“ADAM10 and MMP7 seem to be under canonical Wnt pathway regulation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataOPN and VEGF are regulated by pathways independent of the LRP5/Wnt signalling pathway.
“suggesting that OPN and VEGF are regulated by pathways independent of the LRP5/Wnt signalling pathway.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationCholesterol is essential for neurons, because a lack of cholesterol leads to synapse degeneration, impaired synaptic vesicle exocytosis and neurotransmission, and overall decreased neuronal activity.
“Cholesterol is essential for neurons, because a lack of cholesterol leads to synapse degeneration, impaired synaptic vesicle exocytosis and neurotransmission, and overall decreased neuronal activity.[42][43][44]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [42] Björkhem, 2004, Brain cholesterol: long secret life behind a barrier, Arterioscler Thromb Vasc Biol source
- cites [43] Linetti, 2010, Cholesterol reduction impairs exocytosis of synaptic vesicles, J Cell Sci source
- cites [44] Liu, 2010, Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration, J Neurosci source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenStatistical significance was considered when P < 0.05.
“Statistical significance was considered when P < 0.05.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationLRP5 and the canonical Wnt pathway exert pro-survival roles in peripheral blood leucocytes and induce a pro-survival healing response of cardiomyocytes upon injury.
“LRP5 and the canonical Wnt pathway also exert pro-survival roles in peripheral blood leucocytes 35 and induce a pro-survival healing response of cardiomyocytes upon injury.29,30”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [35] Borrell-Pages, 2015, LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes, Immunol Cell Biol source
- cites [29] Borrell-Pages, 2016, LRP5/canonical Wnt signalling and healing of ischemic myocardium, Basic Res Cardiol source
- cites [30] Badimon, 2019, GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage, PLoS One source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMMP7 participates in the removal of neuronal myelinization, protecting against fibronectin aggregates in multiple sclerosis lesions.
“and in the removal of neuronal myelinization, protecting against fibronectin aggregates in multiple sclerosis lesions.57”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] Wang, 2018, MMP7 cleaves remyelination-impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions, Glia source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
PremisecitationLrp5 -/- mice fed a high fat diet have increased serum cholesterol, increased cholesterol ester accumulation in aortas, and larger aortic lipid infiltrations than hypercholesterolaemic Wt mice.
“Lrp5 -/-mice fed a high fat diet have increased serum cholesterol, increased cholesterol ester accumulation in aortas, and larger aortic lipid infiltrations than hypercholesterolaemic Wt mice. 28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Borrell-Pagès, 2015, LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice, J Cell Mol Med source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the brain, MMP7 participates in the regeneration of injured peripheral nerves.
“In the brain, MMP7 participates in the regeneration of injured peripheral nerves 56”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Wang, 2019, Matrix metalloproteinase 7 promoted Schwann cell migration and myelination after rat sciatic nerve injury, Mol Brain source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMMP7 promotes survival and regeneration in renal tubes, inducing protection against acute kidney injury.
“MMP7 promotes survival and regeneration in renal tubes, inducing protection against acute kidney injury.55”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] Fu, 2019, Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration, Kidney Int source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationADAM10 has a major role in the shedding of β-amyloid protein, preventing the generation of the pathogenic Aβ peptide in Alzheimer's disease.
“has a major role in the shedding of β-amyloid protein, therefore possessing the ability to prevent the generation of the pathogenic Aβ peptide in Alzheimer's disease.53,54”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [53] Lammich, 1999, Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease, Proc Natl Acad Sci U S A source
- cites [54] Kuhn, 2010, ADAM10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons, EMBO J source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenHigh cholesterol-induced functions have been studied in cultured neurons.
“A limitation of this study is that high cholesterol-induced functions have been studied in cultured neurons.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
LRP5 is a receptor of the LDL receptor superfamily that activates the canonical Wnt signalling pathway.
“It is activated by LDL receptor-related protein 5 (LRP5), a receptor of the LDL receptor superfamily.”
The paper relies on this without support.
LRP5, together with Frizzled, binds Wnt ligands or extracellular lipids and induces an intracellular signalling cascade by phosphorylation, allowing β-catenin translocation and LEF binding.
“Together with its coreceptor Frizzled, LRP5 binds specific Wnt ligands or extracellular lipids and induces an intracellular signalling cascade by the phosphorylation of different proteins allowing cytoplasmic β-catenin to translocate to the nucleus and bind the LEF family of transcription factors.”
The paper relies on this without support.
LRP5 is an alternative to the LDLR for cholesterol internalization, and its role in lipid homeostasis has been proven in a variety of organs and tissues.
“We have previously shown that LRP5 is an alternative to the LDLR for cholesterol internalization, and the role of LRP5 in lipid homeostasis has been proven previously in a variety of organs and tissues.”
The paper relies on this without support.
Differentiated SHSY5Y cells are a valid model for human neurons.
“Human neuronal cells were obtained by making a differentiation of neuroblastoma cells SHSY5Y treated with 10 μM of all-trans-RA for 7 days.”
The paper relies on this without support.
The antibodies used for LRP5, β-catenin, and other proteins are specific for their targets.
“primary LRP5 (Abcam, Cambridge, UK) antibodies were added 1 h at room temperature in a moist chamber.”
The paper relies on this without support.
H2O2 and staurosporin induce apoptosis in SHSY5Y cells.
“SHSY5Y cells were incubated with 250 µM H 2 O 2 (Sigma, Macquarie Park, NSW, Australia, #H1009) or 1 µM staurosporin (STP; Sigma #62996) for a further 24 h when apoptotic/necrotic induction was evaluated by flow cytometry.”
The paper relies on this without support.
Cholesterol does not cross the blood-brain barrier in normal physiological conditions.
“Cholesterol does not cross the BBB in normal physiological conditions”
The paper relies on this without support.
The role of LRP5 in the brain has not yet been defined.
“the role of LRP5 in the brain has not yet been defined.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
LRP5 response to lipid loading is both dose-dependent and not concentration-dependent
MinorThe abstract describes the increase in neuronal LRP5 expression as dose-dependent, whereas the results explicitly say it was not concentration-dependent.
“LRP5 expression is increased in a time-and dose-dependent manner after lipid loading in neuronal cells”
“LRP5 expression analyses showed a mild 23.2 ± 2% increase in LRP5 expression at 24 h of DiI-nLDL incubation (Figure 2E), which was not concentration dependent (Figure 2F).”
Conflicting statements about cholesterol crossing the blood-brain barrier
MinorThe discussion says cholesterol does not cross the BBB under normal physiological conditions, but the introduction describes blood-circulating LDL, a cholesterol-carrying particle, crossing the BBB through an LDLR-mediated process.
“Cholesterol does not cross the BBB in normal physiological conditions”
“Blood-circulating LDL molecules can also cross the BBB in a process mediated by the LDLR expressed in caveolin-or clathrin-coated vesicles in specialized BBB-endothelial cells.22”
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Metadata
- Authors
- Borrell-Pages, M., Luquero, A., Vilahur, G., Padró, T., & Badimon, L.
- Affiliations
- Cardiovascular Program ICCC, Sant Pau Institute for Biomedical Research (IIB-Sant Pau) , C/Sant Antoni Maria Claret 167, Barcelona 08025 , Spain
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-10-26
- Volume
- 120
- Issue
- 2
- Pages
- 140-151
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- OpenAlex
- W4387946880
- Cited by
- 10
- References
- 62
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 1
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Spanish Ministerio de Ciencia e Innovación (PID2019-107160RB-I00, PGC 2018-094025-B-I00)
- Instituto de Salud Carlos III (CB16/11/00411, 202-023/AC 209-00054, PI2020-01282)
- Spanish Society of Cardiology (FEC 2022, FEC 2020)
- Fundación Investigación Cardiovascular-Fundación Jesus Serra (PRE2020-096422, PID2019-107160RB-I00)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- canonical Wnt pathway, LRP5, brain cholesterol metabolism, lipoprotein receptors, lipid accumulation, neuronal apoptosis, neuroprotection, CD36, LRP1, β-catenin, LEF1, vascular endothelial growth factor, osteopontin, MMP-7, ADAM10, staurosporine, hydrogen peroxide
- MeSH terms
- Animals, Cholesterol, Homeostasis, Hydrogen Peroxide, Hypercholesterolemia, Neurons, Receptors, LDL, beta Catenin, Mice, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-5
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