The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index; 4 of the 72 sources its claims cite were checked for support.
LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation
Open accessAbstract
Low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1), also known as receptor associated protein (RAP), is an endoplasmic reticulum (ER) chaperone and inhibitor of LDL receptor related protein 1 (LRP1) and related receptors. These receptors have dozens of physiological ligands and cell functions, but it is not known whether cells release LRPAP1 physiologically at levels that regulate these receptors and cell functions. We used mouse BV-2 and human CHME3 microglial cell lines, and found that microglia released nanomolar levels of LRPAP1 when inflammatory activated by lipopolysaccharide or when ER stressed by tunicamycin. LRPAP1 was found on the surface of live activated and non-activated microglia, and anti-LRPAP1 antibodies induced internalization. Addition of 10 nM LRPAP1 inhibited microglial phagocytosis of isolated synapses and cells, and the uptake of Aβ. LRPAP1 also inhibited Aβ aggregation in vitro. Thus, activated and stressed microglia release LRPAP1 levels that can inhibit phagocytosis, Aβ uptake and Aβ aggregation. We conclude that LRPAP1 release may regulate microglial functions and Aβ pathology, and more generally that extracellular LRPAP1 may be a physiological and pathological regulator of a wide range of cell functions.
Overview
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Written from the paper’s full text.
TL;DR
LRPAP1 is released at nanomolar levels by inflammatory- or ER-stressed mouse and human microglial cell lines, and 10 nM extracellular LRPAP1 inhibits microglial phagocytosis of synapses, cells, and Aβ. LRPAP1 also inhibits Aβ fibrillization in vitro, suggesting extracellular LRPAP1 may regulate microglial function and Aβ pathology.
Key findings
- BV-2 microglia released LRPAP1 after LPS (about 2.5-fold increase to ~10 nM) or tunicamycin (~12.5 nM); CHME3 microglia released ~10 nM LRPAP1 after LPS or tunicamycin.
- LRPAP1 was detected on the surface of live BV-2 and CHME3 microglia, and anti-LRPAP1 antibodies were internalized to a peri-nuclear compartment after warming.
- 10 nM LRPAP1 significantly inhibited microglial phagocytosis of pHrodo-labelled synaptosomes and irradiated PC12 cells, and inhibited Aβ uptake by non-activated and LPS-activated BV-2 and CHME3 microglia.
- In thioflavin T assays, 500 nM LRPAP1 significantly and substantially inhibited aggregation/fibrillization of 5 µM Aβ.
Methods
- Used mouse BV-2 and human CHME3 microglial cell lines, treated with LPS, tunicamycin, TNF-α, staurosporine, LRPAP1, Aβ, cytochalasin D, or controls.
- Measured LRPAP1 release by SDS-PAGE western blot with recombinant LRPAP1 standard curves; measured surface LRPAP1 and internalization by immunocytochemistry and flow cytometry.
- Measured phagocytosis of pHrodo-labelled synaptosomes or PC12 cells and Aβ uptake by imaging/flow cytometry; measured Aβ fibrillization by thioflavin T fluorescence over 24 hours; analyzed with ANOVA and post-hoc tests.
Limitations
- The paper states it did not investigate the mechanism of LRPAP1 release except to confirm it was not due to necrosis, nor what surface LRPAP1 binds to, nor the mechanism of antibody internalization.
- The paper states Aβ aggregation was tested with 5 µM Aβ and 500 nM LRPAP1, a 1:10 molar ratio but 100-fold higher than microglia-released levels, so physiological relevance remains to be tested.
- The paper states measurements used BV-2 and CHME3 cell lines, which may differ from microglia in vivo; basal release may have been induced by serum-free culture conditions, and brain extracellular LRPAP1 concentration is unknown.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 72 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation
TAU spreading in mouse brain is mainly mediated by LRP1.
“and TAU spreading in mouse brain is mainly mediated by LRP1 (52).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [52] Rauch, 2020, LRP1 is a master regulator of tau uptake and spread, Nature source
- Premisecitation
Extracellular LRPAP1 inhibits LRP1-mediated transport of Aβ out of the brain.
“and extracellular LRPAP1 is known to inhibit this (62).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [62] Mandrekar, 2009, Microglia mediate the clearance of soluble aβ through fluid phase macropinocytosis, J Neurosci source
The Results section (page unavailable) identifies receptor-associated protein (RAP) as an LRP antagonist and says LRP-1 has been implicated in Aβ uptake and clearance. It does not show that extracellular LRPAP1 inhibits LRP1-mediated transport of Aβ out of the brain; the experiment instead found no effect of RAP on soluble Aβ uptake by microglia. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
Anti-LRPAP1 antibody binding to BV-2 microglia is internalized from the cell surface to a peri-nuclear compartment upon warming to room temperature.
“Warming the cells induced rapid internalization of the anti-LRPAP1 antibody from the cell surface at 0 mins to a peri-nuclear compartment of the cell, presumably lysosomes, at 90 mins ( Figure 3 ).”
- Also stated in: § Abstract · plain
“anti-LRPAP1 antibodies induced internalization”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Rests on an assumption: The anti-LRPAP1 antibodies used specifically detect LRPAP1.
- Also stated in: § Abstract · plain
- Findingown data
In the absence of LRPAP1, Aβ aggregated with standard sigmoidal kinetics.
“In the absence of LRPAP1, Aβ aggregated with standard sigmoidal kinetics ( Figure 8A ).”
Quote in the paperSubstantial claim - Findingown data
10 nM LRPAP1 significantly and substantially inhibits uptake of isolated synapses into BV-2 microglia.
“Both 10 nM and 100 nM LRPAP1 significantly and substantially inhibited uptake of isolated synapses into BV-2 microglia ( Figure 4A ; Supplementary Figure 5A ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Findingown data
10 nM LRPAP1 significantly and substantially inhibits uptake of isolated synapses into CHME3 microglia.
“10 nM LRPAP1 also significantly and substantially inhibited uptake of isolated synapses into CHME3 microglia ( Figure 4B ; Supplementary Figure 5B ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Findingown data
LRPAP1 was found on the surface of live microglia, as measured by binding of anti-LRPAP1 antibodies.
“We found LRPAP1 on the surface of live microglia, as measured by binding of anti-LRPAP1 antibodies.”
Quote in the paperSubstantial claim - Findingown data
Imaging of the wells at the end of the 24-hour incubation revealed standard, Thioflavin T-positive Aβ fibrils in the absence of LRPAP1.
“Imaging of the wells at the end of the 24-hour incubation revealed standard, Thioflavin T-positive Aβ fibrils in the absence of LRPAP1 ( Figure 8B ).”
Quote in the paperSubstantial claim - Findingown data
10 nM LRPAP1 significantly inhibits Aβ uptake in non-activated BV-2 and CHME3 microglia.
“Addition of 10 nM LRPAP1 significantly inhibited Aβ uptake in non-activated BV-2 and CHME3 microglia ( Figures 6 , 7 ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Findingown data
LRPAP1 inhibits Aβ aggregation into fibrils.
“Figure 8 LRPAP1 inhibits fibrillization of Aβ.”
- Also stated in: § Results · hedged
“Thus, LRPAP1 appears to strongly inhibit Aβ aggregation.”
- Also stated in: § Discussion · plain
“and we found that LRPAP1 inhibited Aβ aggregation into fibrils.”
Quote in the paperSubstantial claim - Also stated in: § Results · hedged
- Findingown data
The measured cell surface LRPAP1 did not change with LPS or tunicamycin.
“We found that the measured cell surface LRPAP1 did not change with LPS or tunicamycin”
Quote in the paperNot a substantial claim - Findingown data
10 nM and 100 nM LRPAP1 significantly inhibit uptake of PC12 cells into BV-2 and CHME3 microglia.
“Uptake of PC12 cells into either BV-2 and CHME3 microglia was significantly inhibited by both 10 nM and 100 nM LRPAP1 ( Figures 5A, B ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Findingown data
In the presence of LRPAP1, Aβ aggregation was significantly and substantially inhibited.
“In the presence of LRPAP1, Aβ aggregation was significantly and substantially inhibited.”
Quote in the paperSubstantial claim - Findingown data
LRPAP1 inhibits Aβ uptake by human microglia.
“Figure 7 LRPAP1 inhibits Aβ uptake by human microglia.”
Quote in the paperSubstantial claim - Findingown data
In LPS-activated BV-2 microglia, both 10 and 500 nM LRPAP1 significantly inhibit Aβ uptake.
“In BV-2 microglia, both 10 and 500 nM LRPAP1 significantly inhibited Aβ uptake by activated microglia ( Figure 6 ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Findingown data
LRPAP1 inhibits Aβ aggregation in vitro.
“LRPAP1 also inhibited Aβ aggregation in vitro.”
Quote in the paperSubstantial claim - Findingown data
Nanomolar levels of LRPAP1 (including 10 nM) significantly inhibited microglial phagocytosis of synapses, cells, and Aβ.
“Addition of these nanomolar levels of LRPAP1 to the medium significantly inhibited microglial phagocytosis of synapses, cells, and Aβ.”
- Also stated in: § Discussion · boosted
“We confirmed that 10 nM extracellular LRPAP1 significantly inhibited microglial uptake of Aβ, isolated synapses (synaptosomes) and cells (dead PC12 cells).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Premisecitation
LRPAP1 antagonizes all known natural ligands of the LDL receptor family with nanomolar affinity.
“LRPAP1 antagonizes all known natural ligands of the LDL receptor family with nanomolar affinity (9–14).”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [9] Marakasova, 2021, Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors, J Biol Chem source
- cites [10] Battey, 1994, The 39-kDa receptor-associated protein regulates ligand binding by the very low density lipoprotein receptor, J Biol Chem source
- cites [11] Kounnas, 1992, The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330, J Biol Chem source
- cites [12] Andersen, 2003, Differential binding of ligands to the apolipoprotein E receptor 2, Biochemistry source
- cites [13] Medh, 1995, The 39-kDa receptor-associated protein modulates lipoprotein catabolism by binding to LDL receptors, J Biol Chem source
- cites [14] De Nardis, 2017, Recombinant expression of the full-length ectodomain of LDL receptor-related protein 1 (LRP1) unravels pH-dependent conformational changes and the stoichiometry of binding with receptor-associated protein (RAP), J Biol Chem source
- Interpretationown data
Endogenous cell surface LRPAP1 appears to be bound to receptors whose dimerization results in internalization to lysosomes.
“Thus, endogenous cell surface LRPAP1 appears to be bound to receptors, the dimerization of which results in internalization to lysosomes.”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LRPAP1 antibodies used specifically detect LRPAP1.
- Premisecitation
LRPAP1 can bind Aβ.
“LRPAP1 can bind Aβ (29)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Younkin, 1998, The role of A beta 42 in Alzheimer’s disease, J Physiol Paris source
- Interpretationown data
10 nM extracellular LRPAP1 is sufficient to inhibit microglial phagocytosis of cells.
“Thus, 10 nM extracellular LRPAP1 is sufficient to inhibit microglial phagocytosis of cells.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Premisecitation
Extracellular LRPAP1 can prevent neuronal loss induced by LPS or Aβ.
“We have previously shown that extracellular LRPAP1 can prevent neuronal loss induced by LPS or Aβ (60).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] Fricker, 2012, Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signalling, J Neuroinflamm source
- Interpretationcitation
Extracellular LRPAP1 can potentially block TAU spreading in Alzheimer's disease and other TAU pathologies.
“Thus, extracellular LRPAP1 can potentially block TAU spreading in Alzheimer’s disease and other TAU pathologies.”
Quote in the paperSubstantial claim - Study design and conductown data
Cytochalasin D substantially inhibited Aβ uptake, indicating that most of the uptake was by phagocytosis or endocytosis.
“Cytochalasin D substantially inhibited Aβ uptake indicating that most of the uptake was by phagocytosis or endocytosis ( Figures 6 , 7 ; Supplementary Figure 7 ).”
Quote in the paperNot a substantial claim - Interpretationreasoning
LRPAP1 could regulate uptake of Aβ as an extracellular chaperone.
“and could also regulate uptake as an extracellular chaperone.”
Quote in the paperSubstantial claim - Interpretationown data
10 nM extracellular LRPAP1 is sufficient to substantially inhibit microglial phagocytosis of synapses.
“Thus, 10 nM LRPAP1 is sufficient to substantially inhibit microglial phagocytosis of synapses.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Interpretationreasoning
Extracellular LRPAP1 is likely to be detrimental in Aβ pathology by blocking clearance of extracellular Aβ.
“Thus, extracellular LRPAP1 is likely to be detrimental in Aβ pathology by blocking clearance of extracellular Aβ.”
Quote in the paperSubstantial claim - Study design and conductown data
Cell viability was unaffected by LPS and tunicamycin treatments in CHME3 microglia.
“Cell viability was unaffected by these treatments ( Supplementary Figure 2 ).”
Quote in the paperNot a substantial claim - Premisecitation
LRPAP1 can bind domains II, III and IV of LRP1 in competition with all known ligands.
“while LRPAP1 can bind domains II, III and IV in competition with all known ligands (46–50).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [46] Spuch, 2012, LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer’s disease, Front Physiol source
- cites [47] Obermoeller, 1997, Differential functions of triplicated repeats suggest two independent roles for the receptor-associated protein as a molecular chaperone, J Biol Chem source
- cites [48] Kurasawa, 2015, Cluster III of low-density lipoprotein receptor-related protein 1 binds activated blood coagulation factor VIII, Biochemistry source
- cites [49] Jensen, 2009, Receptor-associated protein (RAP) has two high-affinity binding sites for the low-density lipoprotein receptor-related protein (LRP): consequences for the chaperone functions of RAP, Biochem J source
- cites [50] Meijer, 2007, Functional duplication of ligand-binding domains within low-density lipoprotein receptor-related protein for interaction with receptor associated protein, α2-macroglobulin, factor IXa and factor VIII, Biochim Biophys Acta Proteins Proteom source
- Premisecitation
pHrodo only fluoresces significantly when in the low pH environment of lysosomes.
“pHrodo only fluoresces significantly when in the low pH environment of lysosomes (39).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Miksa, 2009, A novel method to determine the engulfment of apoptotic cells by macrophages using pHrodo succinimidyl ester, J Immunol Methods source
- Premisecitation
LRPAP1 binds Aβ.
“LRPAP1 is known to bind Aβ (64)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Kanekiyo, 2009, Receptor-associated protein interacts with amyloid-β peptide and promotes its cellular uptake, J Biol Chem source
- Interpretationreasoning
Extracellular LRPAP1 potentially regulates the affinity of all physiological ligands for LRP1.
“Thus, extracellular LRPAP1 potentially regulates the affinity of all physiological ligands for LRP1.”
Quote in the paperSubstantial claim - Interpretationreasoning
LRPAP1 could regulate the clearance of Aβ by endothelial cells, neurons, astrocytes and microglia.
“so LRPAP1 could regulate the clearance of Aβ by all these cell types.”
Quote in the paperSubstantial claim - Study design and conductown data
Cytochalasin D strongly inhibited measured phagocytosis, confirming that uptake was by phagocytosis.
“Cytochalasin D, which is known to inhibit phagocytosis by disassembling microtubules (36), strongly inhibited the measured phagocytosis, confirming that uptake was by phagocytosis.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Casella, 1981, Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change, Nature source
- Interpretationcitation
The LRPAP1 released by activated microglia is potentially neuroprotective.
“Thus, the LRPAP1 released by activated microglia is potentially neuroprotective.”
Quote in the paperSubstantial claim- Rests on an assumption: Microglial uptake of Aβ can inflammatory activate microglia, which can be detrimental.
- Interpretationreasoning
LRPAP1 release from stressed microglia and cells generally has wider implications than the release of calreticulin, because it inhibits a range of receptors that have many different cellular functions.
“LRPAP1 release from stressed microglia and cells generally has wider implications than the release of calreticulin, because it inhibits a range of receptors that have many different cellular functions.”
Quote in the paperNot a substantial claim - Study design and conductown data
LRPAP1 does not activate microglia.
“LRPAP1 does not activate microglia ( Supplementary Figure 6 )”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 29
- It may state two separate claims as one. 31
- The quote only partly states this claim. 7
Probably not a substantial claim.
PremisecitationMicroglial phagocytosis of synapses may contribute to synapse loss in neurodegenerative diseases, such as Alzheimer's disease.
“Microglial phagocytosis of synapses may contribute to synapse loss in neurogenerative diseases, such as Alzheimer’s disease (55)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [55] Rajendran, 2018, Microglia-mediated synapse loss in alzheimer’s disease, J Neurosci source
It may state two separate claims as one.
PremisecitationLRP1 can mediate microglial phagocytosis of myelin, which is inhibited by extracellular LRPAP1.
“LRP1 can also mediate microglial phagocytosis of myelin, which is inhibited by extracellular LRPAP1 (63), albeit LRPAP1 was added at supraphysiological levels.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [63] Gaultier, 2009, Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis, J Cell Sci source
The quote only partly states this claim.
Findingown dataIn mouse BV-2 microglia, staurosporine at 1000 nM for 24 hours significantly increases extracellular LRPAP1.
“An inducer of apoptosis, staurosporine, also significantly increased extracellular LRPAP1 ( Figures 1A, B ).”
Quote in the paperNot a substantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
The quote only partly states this claim.
Findingown dataLRPAP1 is present on the surface of intact BV-2 and CHME3 microglia.
“LRPAP1 was found on the surface of live activated and non-activated microglia”
- Also stated in: § Results · plain
“LRPAP1 antibodies bound to the surface of all BV-2 microglia, whereas isotype control antibodies did not bind ( Figures 2A, B ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Rests on an assumption: The anti-LRPAP1 antibodies used specifically detect LRPAP1.
- Also stated in: § Results · plain
The quote only partly states this claim.
Findingown dataIn human CHME3 microglia, LPS at 0.8 μg/mL and tunicamycin at 2 μg/mL for 24 hours induce significant LRPAP1 release to about 10 nM.
“In human CHME3 microglia, we measured LRPAP1 release in response to LPS, tunicamycin and TNF-α, and found LPS and tunicamycin induced significant LRPAP1 release to about 10 nM LRPAP1 ( Figures 1C, D ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
The quote only partly states this claim.
Findingown dataTreating BV-2 or CHME3 microglia with LPS or tunicamycin does not significantly change the measured level of LRPAP1 on the cell surface.
“Treating BV-2 cells with LPS or tunicamycin had no significant effect on the measured level of LRPAP1 on the cell surface.”
- Also stated in: § Results · plain
“LPS had no effect on the apparent level of LRPAP1 on the cell surface ( Figures 2C, D ).”
Quote in the paperNot a substantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Rests on an assumption: The anti-LRPAP1 antibodies used specifically detect LRPAP1.
- Also stated in: § Results · plain
The quote only partly states this claim.
Findingown dataIn mouse BV-2 microglia, tunicamycin at 2 μg/mL for 24 hours significantly increases extracellular LRPAP1 to approximately 12.5 nM.
“An inducer of ER stress, tunicamycin, also significantly increased extracellular LRPAP1, to about 12.5 nM LRPAP1 ( Figures 1A, B ).”
Quote in the paperNot a substantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
The quote only partly states this claim.
Findingown dataIn mouse BV-2 microglia, LPS at 100 ng/mL for 24 hours significantly increases extracellular LRPAP1 about 2.5-fold to approximately 10 nM.
“Activation of BV-2 microglia with the TLR4 agonist lipopolysaccharide (LPS) resulted in a significant increase in extracellular LRPAP1, increasing about 2.5 fold to 10 nM LRPAP1 ( Figures 1A, B ).”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
It may state two separate claims as one.
Findingown dataIn the presence of LRPAP1, there were very few Aβ fibrils, but there was a small amount of Thioflavin T-positive Aβ in amorphous aggregates in the center of the wells.
“In the presence of LRPAP1, there were very few Aβ fibrils, but there was a small amount of Thioflavin T-positive Aβ in amorphous aggregates in the center of the wells ( Figure 8B ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data500 nM LRPAP1 significantly inhibits Aβ uptake in non-activated CHME3 microglia but not BV-2 microglia.
“Addition of 500 nM LRPAP1 significantly inhibited Aβ uptake in non-activated CHME3 microglia ( Figure 7 ), but not BV-2 microglia ( Figure 6 ).”
Quote in the paperNot a substantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
The quote only partly states this claim.
Findingown dataBV-2 and CHME3 microglia released nanomolar levels of LRPAP1 (around 10 nM) into the medium when inflammatory activated with LPS or ER stressed with tunicamycin.
“We found here that BV-2 and CHME3 microglia released nanomolar levels of LRPAP1 into the medium, when inflammatory activated with LPS or ER stressed with tunicamycin.”
- Also stated in: § Discussion · hedged
“Although the released amount of LRPAP1 under stress/inflammation was around 10 nM, this was measured for particular cells in particular conditions at a particular density of cells.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · hedged
It may state two separate claims as one.
Findingown dataIn LPS-activated CHME3 microglia, 10 and 500 nM LRPAP1 inhibit Aβ uptake to a similar extent, but only the inhibition by 10 nM LRPAP1 is significant.
“While in CHME3 microglia, 10 and 500 nM LRPAP1 inhibited Aβ uptake by LPS-activated microglia to a similar extent, but only the inhibition by 10 nM LRPAP1 was significant ( Figure 7 ).”
Quote in the paperNot a substantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingnone givenLRPAP1 release from microglia was not due to necrosis.
“except to confirm that it was not due to necrosis.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataAnti-LRPAP1 antibodies bound to the surface of live microglia, and at temperatures above 4°C, were internalized into a peri-nuclear compartment.
“Anti-LRPAP1 antibodies bound to the surface of live microglia, and at temperatures above 4°C, were internalized into a peri-nuclear compartment, probably lysosomes.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationActivated and ER-stressed microglia can release calreticulin, which activates microglia and acts as an extracellular chaperone for Aβ.
“Recently, we reported that activated and ER-stressed microglia can release the ER-resident chaperone calreticulin, which then activated microglia and acted as an extracellular chaperone for Aβ (30).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Reid, 2022, Brain cells release calreticulin that attracts and activates microglia, and inhibits amyloid beta aggregation and neurotoxicity, Front Immunol source
It may state two separate claims as one.
Interpretationown dataInflammation induced by LPS and ER stress induced by tunicamycin cause LRPAP1 release from mouse and human microglial cell lines, resulting in extracellular LRPAP1 levels of about 10 nM.
“Thus, inflammation (induced by LPS) and ER stress (induced by tunicamycin) appear to cause LRPAP1 release from mouse and human microglial cell lines, resulting in extracellular LRPAP1 levels of about 10 nM.”
- Also stated in: § Abstract · plain
“We used mouse BV-2 and human CHME3 microglial cell lines, and found that microglia released nanomolar levels of LRPAP1 when inflammatory activated by lipopolysaccharide or when ER stressed by tunicamycin.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Also stated in: § Abstract · plain
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationMicroglia express LRP1, which regulates multiple microglial activities including phagocytosis, inflammation and pathology.
“Microglia express LRP1, which regulates multiple microglial activities, including phagocytosis, inflammation and pathology (16, 17).”
Quote in the paperSubstantial claim0 of 2 sources checkedIt may state two separate claims as one.
PremisecitationMicroglial LRP1 mediates Aβ uptake and activation of microglia.
“Microglial LRP1 mediates Aβ uptake and activation of microglia (20–22).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [20] Doens, 2014, Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis, J Neuroinflamm source
- cites [21] Paresce, 1996, Microglial cells internalize aggregates of the Alzheimer’s disease amyloid β-protein via a scavenger receptor, Neuron source
- cites [22] Laporte, 2004, Uptake of Aβ 1–40- and Aβ 1–42-coated yeast by microglial cells: a role for LRP, J Leukoc Biol source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP1 is a plasma membrane receptor mediating endocytosis, phagocytosis, chemotaxis and signaling for extracellular ligands including ApoE, lipoproteins, α2-macroglobulin, proteases, extracellular matrix proteins, growth factors, complement factors, heat shock proteins and dozens of other natural ligands.
“Low density lipoprotein (LDL) receptor related protein 1 (LRP1) is a plasma membrane receptor mediating endocytosis, phagocytosis, chemotaxis and signaling for extracellular ligands, including apolipoprotein E (ApoE), lipoproteins, α2-macroglobulin, proteases, extracellular matrix proteins, growth factors, complement factors, heat shock proteins and dozens of other natural ligands (1–5).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [1] Harris-White, 2005, Low density lipoprotein receptor-related proteins (LRPs), Alzheimer’s and cognition, Curr Drug Targets CNS Neurol Disord source
- cites [2] Basu, 2001, CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin, Immunity source
- cites [3] Strickland, 2002, Diverse roles for the LDL receptor family, Trends Endocrinol Metab source
- cites [4] Fernandez-Castaneda, 2013, Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris, J Biol Chem source
- cites [5] Strickland, 1990, Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor, J Biol Chem source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataSecondary antibodies did not bind in the absence of the primary antibody.
“Secondary antibodies did not bind in the absence of the primary antibody ( Supplementary Figure 3 ).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningIf microglia can release LRPAP1 up to an extracellular concentration of 10 nM, then 10 nM extracellular LRPAP1 might inhibit endocytosis or phagocytosis mediated by LRP1, LRP2, ApoER2 and VLDLR.
“Thus, if microglia can release LRPAP1 up to an extracellular concentration of 10 nM, as we found, then we might expect 10 nM extracellular LRPAP1 to inhibit endocytosis or phagocytosis mediated by LRP1, LRP2, ApoER2 and VLDLR.”
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.
PremisecitationAlzheimer's disease is the main cause of dementia, and is driven in part by the aggregation of Aβ.
“Alzheimer’s disease is the main cause of dementia, and is driven in part by the aggregation of Aβ (18, 19).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. It may state two separate claims as one.
PremisecitationLRP1 has four potential ligand-binding domains: domain I does not bind any known ligands, domains II and IV bind all known ligands, and domain III binds ApoE and blood coagulation factor VIII.
“LRP1 has four potential ligand-binding domains: domain I does not bind any known ligands, domains II and IV binds all known ligands (46), and domain III binds ApoE and blood coagulation factor VIII (47, 48)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [46] Spuch, 2012, LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer’s disease, Front Physiol source
- cites [47] Obermoeller, 1997, Differential functions of triplicated repeats suggest two independent roles for the receptor-associated protein as a molecular chaperone, J Biol Chem source
- cites [48] Kurasawa, 2015, Cluster III of low-density lipoprotein receptor-related protein 1 binds activated blood coagulation factor VIII, Biochemistry source
Probably not a substantial claim.
PremisecitationNeurons, astrocytes and microglia use LRP1 to uptake Aβ.
“neurons, astrocytes and microglia use LRP1 to uptake Aβ (28)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Kanekiyo, 2014, The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease, Front Aging Neurosci source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationAntibodies binding to some cell surface receptors result in antibody internalization because dimerization of the receptor is sufficient to activate the receptor, resulting in internalization into endosome and lysosomes.
“Antibodies binding to some cell surface receptors result in antibody internalization because dimerization of the receptor is sufficient to activate the receptor, resulting in internalization into endosome and lysosomes (37).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Spaargaren, 1991, Antibody-induced dimerization activates the epidermal growth factor receptor tyrosine kinase, J Biol Chem source
It may state two separate claims as one.
Study design and conductown dataBlocking Fc receptors had no effect on anti-LRPAP1 antibody binding, indicating antibody binding is not mediated by Fc receptors.
“Blocking Fc receptors had no effect on anti-LRPAP1 antibody binding ( Supplementary Figure 4 ), indicating the antibody binding is not mediated by Fc receptors.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe concentration of LRPAP1 normally found by mass spectrometry in human blood plasma is about 800 ng/l, equivalent to about 20 pM.
“The concentration of LRPAP1 normally found by mass spectrometry in human blood plasma is about 800 ng/l, equivalent to about 20 pM (PeptideAtlas)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites PeptideAtlas
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. It may state two separate claims as one.
InterpretationcitationIf LRPAP1 is released during demyelination it might inhibit myelin clearance, which is thought to be important in multiple sclerosis.
“Thus, if LRPAP1 is released during demyelination it might inhibit myelin clearance, which is thought to be important in multiple sclerosis (63).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] Gaultier, 2009, Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis, J Cell Sci source
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 givenNeither BV-2 nor CHME3 cell line is listed as a commonly misidentified cell line by the International Cell Line Authentication Committee.
“Neither cell line is listed as a commonly misidentified cell line by the International Cell Line Authentication Committee.”
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.
PremisecitationLRPAP1 is present in the cerebrospinal fluid, and mildly decreases with minor cognitive impairment and mildly increases in Alzheimer's disease.
“LRPAP1 is also present in the cerebrospinal fluid, and mildly decreases with minor cognitive impairment and mildly increases in Alzheimer’s disease (66).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] del Campo, 2022, CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels, Nat Aging source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationEndogenous LRPAP1 is found bound to LRP1 on the surface of live cells, and blocks the binding of extracellular ligands of LRP1.
“It has previously been found that endogenous LRPAP1 is found bound to LRP1 on the surface of live cells, and blocks the binding of extracellular ligands of LRP1 (44).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Williams, 1992, A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein, J Biol Chem source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationInflamed and stressed microglia release the ER chaperone calreticulin, which inhibits Aβ aggregation and affects microglial functions.
“The research reported here mirrors our previous finding that inflamed and stressed microglia release the ER chaperone calreticulin, which inhibits Aβ aggregation and affects microglial functions (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Reid, 2022, Brain cells release calreticulin that attracts and activates microglia, and inhibits amyloid beta aggregation and neurotoxicity, Front Immunol source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLPS can induce microglia to release another ER-resident chaperone, calreticulin.
“We recently reported that LPS can induce microglia to release another ER-resident chaperone, calreticulin (30)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Reid, 2022, Brain cells release calreticulin that attracts and activates microglia, and inhibits amyloid beta aggregation and neurotoxicity, Front Immunol source
It may state two separate claims as one.
Interpretationown dataLRPAP1 release from microglia potentially regulates microglial phagocytosis and Aβ pathology.
“Thus, LRPAP1 release from microglia potentially regulates microglial phagocytosis and Aβ pathology.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of LRPAP1 on microglial phagocytosis and Aβ aggregation observed in cell lines and in vitro assays are relevant to microglia and Aβ pathology in vivo.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPhysiological ligands may activate LRP1 and related receptors by binding two or more receptor molecules, resulting in dimerization of the intracellular domain, leading to phosphorylation of tyrosine residues in these domains, which in turn recruit other signaling or scaffolding proteins.
“Physiological ligands may activate LRP1 and related receptors by binding two or more receptor molecules, resulting in dimerization of the intracellular domain, leading to phosphorylation of tyrosine residues in these domains, which in turn recruit other signaling or scaffolding proteins (51).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Weiss, 1998, Switching signals on or off by receptor dimerization, Cell source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGenetic variants of LRPAP1 have been linked to dementia, late-onset Alzheimer's disease and Parkinson's disease.
“Genetic variants of LRPAP1 have been linked to dementia, late-onset Alzheimer’s disease and Parkinson’s disease (23–25)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [23] Singh, 2014, APOE and LRPAP1 gene polymorphism and risk of Parkinson’s disease, Neurological Sci source
- cites [24] Pandey, 2008, LRP-associated protein gene (LRPAP1) and susceptibility to degenerative dementia, Genes Brain Behav source
- cites [25] Sánchez, 2001, Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease, Am J Med Genet source
It may state two separate claims as one.
PremisecitationCalreticulin and LRPAP1 both bind LRP1, but calreticulin is an agonist and co-receptor with LRP1, while LRPAP1 is an antagonist of LRP1.
“Calreticulin and LRPAP1 both bind LRP1, but calreticulin is an agonist and co-receptor with LRP1 (67, 68), while LRPAP1 is an antagonist of LRP1.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [67] Donnelly, 2006, Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus, Arthritis Rheum source
- cites [68] Gardai, 2005, Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte, Cell source
It may state two separate claims as one.
InterpretationcitationIf extracellular LRPAP1 levels increase, potentially as a result of inflammation, this might inhibit Aβ export from the brain, potentially increasing Aβ levels within the brain.
“Thus, if extracellular LRPAP1 levels increase, potentially as a result of inflammation, this might inhibit Aβ export from the brain, potentially increasing Aβ levels within the brain.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataActivated and stressed microglia release LRPAP1 levels that can inhibit phagocytosis, Aβ uptake and Aβ aggregation.
“Thus, activated and stressed microglia release LRPAP1 levels that can inhibit phagocytosis, Aβ uptake and Aβ aggregation.”
- Also stated in: § Highlights · plain
“Stressed microglia release LRPAP1 at levels that inhibit microglial phagocytosis of synapses and cells, and reduce amyloid beta fibrillization and clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Rests on an assumption: Endogenous LRPAP1 released by microglia is active and inhibits receptors similarly to recombinant LRPAP1.
- Also stated in: § Highlights · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP1 on endothelial cells of the blood-brain barrier mediates export of Aβ out of the brain.
“LRP1 on endothelial cells of the blood-brain barrier mediates export of Aβ out of the brain (27)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Storck, 2016, Endothelial LRP1 transports amyloid-β1-42 across the blood-brain barrier, J Clin Invest source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCytochalasin D is known to inhibit phagocytosis by disassembling microtubules.
“Cytochalasin D, which is known to inhibit phagocytosis by disassembling microtubules (36)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Casella, 1981, Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change, Nature source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationMicroglial phagocytosis of synapses is important in brain development, and disruption of this phagocytosis may lead to developmental pathologies, such as autism.
“Microglial phagocytosis of synapses is important in brain development, and disruption of this phagocytosis may lead to developmental pathologies, such as autism (54).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Wang, 2018, Synaptic dysfunction in complex psychiatric disorders: From genetics to mechanisms, Genome Med source
It may state two separate claims as one.
PremisecitationMicroglia express LRP1, ApoER2, VLDLR and LDLR.
“Microglia have been shown to express LRP1, ApoER2, VLDLR and LDLR (53)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Fan, 2001, Expression and regulation of apolipoprotein E receptors in the cells of the central nervous system in culture: A review, J Am Aging Assoc source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationER stress can induce the release of calreticulin and other ER-resident chaperones.
“others have shown that ER stress can induce the release of calreticulin and other ER-resident chaperones (30, 45).”
Quote in the paperNot a substantial claim0 of 2 sources checkedIt may state two separate claims as one.
PremisecitationReported dissociation constants (KD) of LRPAP1 for LRP1, LRP-2, ApoER2, VLDL receptor, and LDL receptor are 1-14 nM, 8 nM, 5 nM, 0.7 nM, and 250 nM, respectively.
“The dissociation constant (KD) of LRPAP1 for these receptors, reported in the literature, are as follows: LRP1 [1-14 nM (9, 14)], LRP-2 [KD: 8 nM (11)], ApoER2 [KD: 5 nM (12)], VLDL receptor [KD: 0.7 nM (10)] and LDL receptor [KD: 250 nM (13)].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [9] Marakasova, 2021, Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors, J Biol Chem source
- cites [14] De Nardis, 2017, Recombinant expression of the full-length ectodomain of LDL receptor-related protein 1 (LRP1) unravels pH-dependent conformational changes and the stoichiometry of binding with receptor-associated protein (RAP), J Biol Chem source
- cites [11] Kounnas, 1992, The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330, J Biol Chem source
- cites [12] Andersen, 2003, Differential binding of ligands to the apolipoprotein E receptor 2, Biochemistry source
Probably not a substantial claim.
PremisecitationMicroglial uptake of Aβ is partly mediated by LRP1.
“Microglial uptake of Aβ is known to be partly mediated by LRP1 (22)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Laporte, 2004, Uptake of Aβ 1–40- and Aβ 1–42-coated yeast by microglial cells: a role for LRP, J Leukoc Biol source
It may state two separate claims as one.
Interpretationown dataLRPAP1 release may regulate microglial functions and Aβ pathology, and extracellular LRPAP1 may be a physiological and pathological regulator of a wide range of cell functions.
“We conclude that LRPAP1 release may regulate microglial functions and Aβ pathology, and more generally that extracellular LRPAP1 may be a physiological and pathological regulator of a wide range of cell functions.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
- Rests on an assumption: Endogenous LRPAP1 released by microglia is active and inhibits receptors similarly to recombinant LRPAP1.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP1 and related LDL family receptors regulate a wide range of cellular processes, including endocytosis, phagocytosis, chemotaxis and signaling in response to dozens of ligands.
“Outside the brain, LRP1 and related LDL family receptors regulate a wide range of cellular processes, including endocytosis, phagocytosis, chemotaxis and signaling in response to dozens of ligands (1–4).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [1] Harris-White, 2005, Low density lipoprotein receptor-related proteins (LRPs), Alzheimer’s and cognition, Curr Drug Targets CNS Neurol Disord source
- cites [2] Basu, 2001, CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin, Immunity source
- cites [3] Strickland, 2002, Diverse roles for the LDL receptor family, Trends Endocrinol Metab source
- cites [4] Fernandez-Castaneda, 2013, Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris, J Biol Chem source
Probably not a substantial claim.
PremisecitationLRP1, expressed by the blood-brain barrier, mediates transport of Aβ out of the brain.
“LRP1, expressed by the blood-brain barrier, is known to mediate transport of Aβ out of the brain (61)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [61] Ma, 2018, Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism, Mol Neurodegener source
It may state two separate claims as one.
Interpretationown data10 nM extracellular LRPAP1 inhibits Aβ uptake by microglia, and this appears to be a saturating dose.
“Thus, 10 nM extracellular LRPAP1 inhibits Aβ uptake by microglia, and this appears to be a saturating dose.”
Quote in the paperSubstantial claim- Rests on an assumption: BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
Probably not a substantial claim.
PremisecitationLRP1 and related receptors of the LDL receptor family mediate endocytosis or phagocytosis of a wide range of extracellular targets, including Aβ, TAU, ApoE and apoptotic cells, via ligand binding to these receptors.
“LRP1 and related receptors of the LDL receptor family are known to mediate endocytosis or phagocytosis of a wide range of extracellular targets, including Aβ, TAU, ApoE and apoptotic cells, via ligand binding to these receptors (6, 28, 52).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Go, 2012, Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis, Yale J Biol Med
- cites [28] Kanekiyo, 2014, The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease, Front Aging Neurosci source
- cites [52] Rauch, 2020, LRP1 is a master regulator of tau uptake and spread, Nature source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSuch LRPAP1 variants may be unable to bind LRP1 correctly.
“and such variants may be unable to bind LRP1 correctly (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Aldahmesh, 2013, Mutations in LRPAP1 are associated with severe myopia in humans, Am J Hum Genet source
It may state two separate claims as one.
PremisecitationLRP1 binds and mediates uptake of oligomeric TAU into cells, and this is fully blocked by LRPAP1 with an inhibition constant (Ki) of 5 nM extracellular LRPAP1.
“LRP1 is known to bind and mediate uptake of oligomeric TAU into cells, and this is fully blocked by LRPAP1 with an inhibition constant (Ki) of 5 nM extracellular LRPAP1 (52)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Rauch, 2020, LRP1 is a master regulator of tau uptake and spread, Nature source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPlasma levels of LRPAP1 are negatively correlated with cognition in some conditions.
“and plasma levels are negatively correlated with cognition in some conditions (65).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Llaurador-Coll, 2023, Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome, Geroscience source
The paper relies on this without support.
BV-2 and CHME3 cell lines are valid models of microglia for studying LRPAP1 release and phagocytosis.
“The immortalized cell lines BV-2 (ECACC Cat# 0356, RRID: CVCL_0182) and CHME3 (ATCC Cat# CRL-3304, RRID: CVCL_II76) were maintained as previously described (31, 32).”
The paper relies on this without support.
The anti-LRPAP1 antibodies used specifically detect LRPAP1.
“antibodies to human and mouse LRPAP1 were from SinoBiological (Beijing, China)”
The paper relies on this without support.
Endogenous LRPAP1 released by microglia is active and inhibits receptors similarly to recombinant LRPAP1.
“Addition of 10 nM LRPAP1 inhibited microglial phagocytosis of isolated synapses and cells, and the uptake of Aβ.”
“microglia released nanomolar levels of LRPAP1 when inflammatory activated by lipopolysaccharide or when ER stressed by tunicamycin.”
The paper relies on this without support.
Microglial uptake of Aβ can inflammatory activate microglia, which can be detrimental.
“However, microglial uptake of Aβ can also inflammatory activate microglia, which can potentially be detrimental.”
The paper relies on this without support.
The effects of LRPAP1 on microglial phagocytosis and Aβ aggregation observed in cell lines and in vitro assays are relevant to microglia and Aβ pathology in vivo.
“Our measurement of LRPAP1 release was in BV-2 and CHME3 microglial cell lines, which may differ significantly from microglia in vivo, so it would be useful to expand these measurements to primary cells, other cell types and the brain in vivo.”
“we cannot rule out that the basal release of LRPAP1 that we found in culture was induced by the serum-free conditions in which release was measured.”
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.
Cytochalasin D mechanism conflicts with the cited reference title
MinorThe results say cytochalasin D disassembles microtubules, but the paper's cited reference 36 describes inhibition and depolymerization of actin filaments.
“Cytochalasin D, which is known to inhibit phagocytosis by disassembling microtubules (36), strongly inhibited the measured phagocytosis, confirming that uptake was by phagocytosis.”
“36. Casella JF Flanagan MD Lin S. Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change.”
Aβ fibrillization measurement interval differs between methods and caption
MinorThe methods state that fluorescence was read every 10 minutes, whereas the Figure 8 caption says it was measured every hour.
“Fluorescence readings (absorbance: 440 nm; emission: 480 nm) were taken every 10 minutes for 24 hours, with 10 seconds of orbital shaking preceding each measurement.”
“Every hour, after orbital shaking, thioflavin T fluorescence was measured.”
Figure 6 describes two different Aβ uptake measures
MinorThe caption identifies the reported measure as percentage median fluorescence intensity, then describes the data as the mean percentage of cells containing Aβ. These are different flow-cytometry measures.
“Data presented a mean % of cells containing Aβ, with error bars representing the SEM of 4 independent experiments.”
“(B) Percentage median fluorescence intensity by BV-2 microglia, as a measure of Aβ uptake, was measured by flow cytometry using the YL1-A fluorescence channel and normalized to the ‘- LPS’ treated control.”
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Metadata
- Authors
- Reid, K. M., & Brown, G. C.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Brown, Guy C.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2023-11-16
- Volume
- 14
- Pages
- 1286474-1286474
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC10687467
- OpenAlex
- W4388721994
- Cited by
- 13
- References
- 68
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Biotechnology and Biological Sciences Research Council (BBSRC BB/M011194/1)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- LRPAP1, receptor-associated protein, microglia, extracellular release, microglial phagocytosis, amyloid-beta, amyloid-beta aggregation, endoplasmic reticulum stress, lipopolysaccharide stimulation, tunicamycin, LRP1, Alzheimer's disease
- MeSH terms
- Animals, Carrier Proteins, Cell Line, Cells, Cultured, Humans, Phagocytosis, Amyloid beta-Peptides, Microglia, LDL-Receptor Related Protein-Associated Protein, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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