The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; 5 of the 33 sources its claims cite were checked for support.
The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates
Open accessPublished version of a preprint
Abstract
Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR), and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer's disease (AD), where apoE is involved in neuronal uptake and accumulation of Aβ42, eventually cascading into neurodegeneration, synaptic dysfunction, and ultimately, dementia. We hypothesize that the intact Sigma-2 receptor complex-TMEM97, PGRMC1, and LDLR-is necessary for internalization of apoE and Aβ42 monomers (mAβ42) and oligomers (oAβ42), and the disruption of the receptor complex inhibits uptake. The results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4. The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons. The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal Aβ42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
The TMEM97/PGRMC1/LDLR complex is present in primary rat cortical neurons and human brain tissue and mediates cellular uptake of Aβ42 monomers and oligomers, with apoE-dependent and apoE-independent components. Disrupting the complex genetically or pharmacologically reduces Aβ42 and apoE uptake, suggesting a potential AD therapeutic target.
Key findings
- The trimeric TMEM97/PGRMC1/LDLR complex was detected in DIV21 primary rat cortical neurons by proximity ligation assay and in human frontal cortex tissue from cognitively normal and AD subjects.
- In HeLa control, TMEM97 KO, PGRMC1 KO, and TMEM97/PGRMC1 DKO cells, knockout significantly decreased uptake of mAβ42 and oAβ42 alone or with apoE3; fAβ42 uptake was less affected.
- In primary rat cortical neurons, 500 nM RHM-4, SW43, or AG-205 reduced mAβ42 and oAβ42 uptake alone and with apoE2, apoE3, or apoE4; Aβ42 uptake with apoE isoforms ranked apoE2 < apoE3 < apoE4.
- Radiolabeled RHM-4 bound primary rat neuron homogenates with Kd = 1.37 nM and Bmax = 1448 fmol/mg; ligand affinities reported were RHM-4 Kd ~0.2 nM, SW43 Kd ~12 nM, and AG205 Kd ~1 μM against Sigma2R.
Methods
- Uptake studies used HeLa CRISPR/Cas9 control, TMEM97 KO, PGRMC1 KO, and TMEM97/PGRMC1 DKO cells, plus DIV21 primary rat cortical neurons; human postmortem frontal cortex samples included cognitively normal and AD cases.
- Aβ42 monomers, oligomers, and fibrils were prepared and characterized by TEM and dot blot; apoE2, apoE3, and apoE4 were lipidated with DMPC and complexed with Aβ42. Cells were treated with 1000 nM mAβ42, oAβ42, or fAβ42 ± 250 nM apoE for 24 h, or with 500 nM RHM-4, SW43, or AG-205; uptake was quantified by Aβ42 and apoE ELISA normalized to total protein.
- Additional methods included confocal microscopy with fluorescent oAβ42/fAβ42, proximity ligation assays, and [125I]RHM-4 saturation binding (0.02–9 nM; nonspecific binding with 10 μM DTG); data analyzed by one-way or two-way ANOVA with Tukey post-hoc test and ROUT outlier method (Q = 1%).
Limitations
- The paper states that future animal-model studies are needed to test in vivo disruption of the complex, apoE isoform-specific effects, LRP1 involvement, lipid homeostasis, and disease-stage effects; it also notes the caveat that once AD symptoms manifest, intervention may be too late.
- Evident from the text: the main functional evidence comes from HeLa cells and primary rat neurons, with human data limited to postmortem tissue showing complex presence rather than uptake function; no in vivo efficacy, behavioral, or neurotoxicity outcomes are reported.
- Evident from the text: the study does not directly test cell-to-cell transfer or other aggregated proteins such as alpha-synuclein and tau, which the authors say are under investigation.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
5 of 33 cited sources checked · 0 supported · 1 flagged · accuracy not yet measured
- Findingreasoning
ApoE was not inhibited by TMEM97 or PGRMC1 ligands when in complex with fAβ42.
“Curiously, apoE was not inhibited by the TMEM97 or PGRMC1 ligands when in a complex with fAβ42”
Quote in the paperNot a substantial claim - Findingreasoning
Loss or pharmacological inhibition of TMEM97 and/or PGRMC1 decreases uptake of mAβ42, oAβ42, and apoE in primary neurons.
“The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons.”
Quote in the paperSubstantial claim- Rests on an assumption: Loss or pharmacological inhibition of TMEM97 and/or PGRMC1 disrupts the TMEM97/PGRMC1/LDLR complex.
- Findingown data
Uptake of Aβ42 in complex with apoE isoforms increased in rank order apoE2 < apoE3 < apoE4.
“There was an increase in uptake of Aβ42 in complex with the various apoE isoforms in a rank order of apoE2 < apoE3 < apoE4”
Quote in the paperNot a substantial claim - Findingown data
Scramble/Cas9 cells showed significantly more uptake of oAβ42 compared to knockout cell lines at all time points (10, 30, and 60 minutes).
“Scramble/Cas9 cells showed significantly more uptake of oligomers compared to the knockout cell lines at all time points since the internalized signal increased over time (Fig 2A).”
Quote in the paperSubstantial claim - Findingown data
All compounds inhibited the mAβ42-ApoE complex with all three apoE isoforms.
“all compounds were able to inhibit the mAβ42-ApoE complex with all three isoforms (E2, E4, E4)”
Quote in the paperSubstantial claim
- Findingown data
mAβ42 is more efficiently taken up by cells when it is in a complex with apoE3.
“The first observation of these experiments was mAβ42 is more efficiently taken up by cells when it is in a complex with apoE3.”
Quote in the paperSubstantial claim - Findingown data
The TMEM97/PGRMC1/LDLR trimeric complex is intact in primary rat cortical neurons.
“we confirmed that the trimeric TMEM97/PGRMC1/LDLR complex is intact in primary rat cortical neurons (Fig. 3C)”
Quote in the paperSubstantial claim - Findingreasoning
fAβ42 was not readily taken up by cultured neurons.
“fAβ42 was not readily taken up by cultured neurons”
Quote in the paperSubstantial claim - Findingown data
Radiolabeled RHM-4 bound to primary rat neuron homogenates with an observed Kd of 1.37 nM and Bmax of 1448 fmol/mg.
“Radiolabeled RHM-4 was able to bind with homogenates of primary rat neurons (Fig. 3 B), with an observed Kd of 1.37 nM and a Bmax of 1448 fmol/mg”
Quote in the paperSubstantial claim - Findingown data
The trimeric complex of TMEM97, PGRMC1, and LDLR is present in primary rat cortical neurons, as shown by pairwise proximity ligation assay interactions.
“We identified the presence of the trimeric complex in a pairwise proximity ligation assay (Fig 3 C), as evident by the interaction of LDLR and PGRMC1, LDLR and TMEM97, and TMEM97 and PGRMC1.”
Quote in the paperSubstantial claim - Findingown data
Pharmacological inhibition of TMEM97 and PGRMC1 results in decreased uptake of mAβ42 and all apoE isoforms in primary neurons.
“Results indicate that pharmacological inhibition of TMEM97 and PGRMC1 results in a decrease in mAβ42 and all apoE isoforms.”
Quote in the paperSubstantial claim - Findingreasoning
The compounds did not have an effect on cell-associated fAβ42 alone or in complex with apoE.
“the compounds did not have an effect on cell associated fAβ42 alone or in a complex with apoE.”
Quote in the paperNot a substantial claim - Findingown data
Uptake of the mAβ42/apoE3 complex was significantly decreased in TMEM97 KO, PGRMC1 KO, and DKO HeLa cell lines compared to Scramble/Cas9 control.
“Uptake of the mAβ42/apoE3 complex was significantly decreased in the TMEM97 KO, PGRMC1 KO, and DKO cell lines when compared to Scramble/Cas9.”
Quote in the paperSubstantial claim - Findingown data
The TMEM97/PGRMC1/LDLR trimeric complex is intact in human brain tissue samples from both cognitively normal subjects and a subject with AD.
“We observed that the trimeric complex is intact in both human tissue samples”
Quote in the paperSubstantial claim - Findingown data
The same trend of decreased uptake with inhibition was observed for oAβ42 in the presence and absence of apoE isoforms.
“The same trend was observed for oAβ42 in the presence and absence of the apoE isoforms (Fig 4 B and E).”
Quote in the paperSubstantial claim - Findingown data
Uptake of oAβ42, and to a lesser extent fAβ42, alone and in complex with apoE3 was significantly decreased in the knockout cell lines.
“Uptake of oAβ42, and to a lesser extent fAβ42, alone and when in complex with apoE3 was also significantly decreased in the knockout cell lines.”
Quote in the paperSubstantial claim - Findingown data
The compounds resulted in significantly less uptake of apoE3 alone or in complex with any Aβ42 aggregated state.
“The compounds also resulted in significantly less uptake of apoE3 alone or when in a complex with any of the Aβ42 aggregated states (Fig 1D).”
Quote in the paperSubstantial claim - Findingown data
Internalized oAβ42 was associated with MAP2 positive neurons.
“We observed that the internalized oAβ42 was associated with MAP2 positive neurons (SI Appendix, Fig. S2 and S3).”
Quote in the paperNot a substantial claim - Findingown data
The uptake of mAβ42 in HeLa cells was enhanced by the presence of apoE.
“The uptake of mAβ42 in HeLa cells was enhanced by the presence of apoE (Fig. 1 A and C)”
Quote in the paperNot a substantial claim - Findingown data
oAβ42 did not require apoE to be taken up by HeLa cells or primary neurons.
“Conversely, oAβ42 did not require apoE to be taken up by HeLa cells (Fig. 1 A and C) or primary neurons (Fig. 4 B and E).”
Quote in the paperNot a substantial claim - Findingown data
In both the HeLa model system and primary neuronal cells, RHM-4, SW43, and AG-205 reduce uptake of mAβ42 and oAβ42 alone and when in a complex with apoE.
“In both the HeLa model system and primary neuronal cells, RHM-4, SW43, and AG-205 were able to reduce uptake of mAβ42 and oAβ42 alone and when in a complex with apoE.”
Quote in the paperSubstantial claim - Findingown data
Knocking out TMEM97 and/or PGRMC1 in HeLa cells resulted in a marked decrease of mAβ42 and oAβ42 uptake alone or when in a complex with apoE.
“Knocking out TMEM97 and/or PGRMC1 in HeLa cells resulted in a marked decrease of mAβ42 and oAβ42 uptake alone or when in a complex with apoE.”
Quote in the paperSubstantial claim - Findingown data
Uptake of apoE3 was significantly less in the knockout cell lines compared to Scramble/Cas9 control.
“Uptake of apoE3 was also significantly less in the knockout cell lines compared to Scramble/Cas9 control cell (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
The reliance on apoE as a chaperone for mAβ42 uptake was not observed in primary cultured neurons.
“this reliance on apoE as a chaperone for uptake was not observed in the primary cultured neurons (Fig. 4 A and D).”
Quote in the paperNot a substantial claim - Premisecitation
The intact TMEM97/PGRMC1/LDLR complex is required for efficient uptake of LDL and lipoproteins such as apoE.
“this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE)”
- Also stated in: § INTRODUCTION · plain
“this intact complex is important for the efficient uptake of low density lipoprotein (LDL)”
- Also stated in: § TMEM97 and PGRMC1 play a role in Aβ42 and apoE uptake · plain
“this complex is necessary for efficient uptake of LDL”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, Metz T, Carlin S et al (2018) Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 8:16845. https://doi.org/10.1038/s41598-018-35430-3 source
- Also stated in: § INTRODUCTION · plain
- Premisecitation
TMEM97 and PGRMC1 are expressed much higher in neurons than in glial cells.
“previous studies have shown that they are expressed much higher in neurons than in glial cells [6, 7, 47].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd et al (2014) Alzheimer's therapeutics targeting amyloid beta 1–42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9:e111898. https://doi.org/10.1371/journal.pone.0111898 source
A check is scheduled.
- cites [7] Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R et al (2014) Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 9:e111899. https://doi.org/10.1371/journal.pone.0111899 source
A check is scheduled.
- cites [47] Zeng C, Garg N, Mach RH (2016) The PGRMC1 protein level correlates with the binding activity of a Sigma-2 fluorescent probe (SW120) in rat brain cells. Mol Imaging Biol 18:172–179. https://doi.org/10.1007/s11307-015-0891-z source
- Interpretationreasoning
Reducing neuronal load of Aβ42 may potentially inhibit the neurotoxic effects of Aβ42 accumulation and aggregation.
“Reducing neuronal load of Aβ42 may potentially inhibit the neurotoxic effects of Aβ42 accumulation and aggregation.”
Quote in the paperSubstantial claim - Premisecitation
TMEM97 and PGRMC1 form a complex with the LDL receptor (LDLR).
“Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR)”
- Also stated in: § INTRODUCTION · plain
“Our previous work has shown that Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR) [8]”
- Also stated in: § TMEM97 and PGRMC1 play a role in Aβ42 and apoE uptake · hedged
“Our previous work indicated that TMEM97 and PGRMC1 form a trimeric complex with the LDLR”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, Metz T, Carlin S et al (2018) Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 8:16845. https://doi.org/10.1038/s41598-018-35430-3 source
- Also stated in: § INTRODUCTION · plain
- Premisecitation
TMEM97 and PGRMC1 specific ligands bind their targets more prominently, and with much higher affinity, in neurons than in glial cells.
“Moreover, TMEM97 and PGRMC1 specific ligands bind their targets more prominently, and with much higher affinity, in neurons than in glial cells [6, 7, 47].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd et al (2014) Alzheimer's therapeutics targeting amyloid beta 1–42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9:e111898. https://doi.org/10.1371/journal.pone.0111898 source
A check is scheduled.
- cites [7] Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R et al (2014) Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 9:e111899. https://doi.org/10.1371/journal.pone.0111899 source
A check is scheduled.
- cites [47] Zeng C, Garg N, Mach RH (2016) The PGRMC1 protein level correlates with the binding activity of a Sigma-2 fluorescent probe (SW120) in rat brain cells. Mol Imaging Biol 18:172–179. https://doi.org/10.1007/s11307-015-0891-z source
- Interpretationreasoning
The lack of inhibition of apoE in complex with fAβ42 may be because apoE accumulates on the surface with fAβ42 and is not internalized.
“which may be due to the fact that it accumulates on the surface along with fAβ42 and is not internalized.”
Quote in the paperNot a substantial claim - Interpretationown data
The inhibition of the mAβ42-ApoE complex by all compounds indicates potential therapeutic use in patients with any of the apoE alleles.
“indicating potential therapeutic use in patients with any of the apoE alleles.”
Quote in the paperSubstantial claim - Interpretationown data
The intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4.
“The results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4.”
Quote in the paperSubstantial claim- Rests on an assumption: Loss or pharmacological inhibition of TMEM97 and/or PGRMC1 disrupts the TMEM97/PGRMC1/LDLR complex.
- Interpretationown data
TMEM97 and PGRMC1 mediate internalization of Aβ42 and apoE3.
“These results indicate that TMEM97 and PGRMC1 mediate internalization of Aβ42 and apoE3”
Quote in the paperSubstantial claim - Interpretationown data
The results in the HeLa model system and primary cultured neurons are representative of the conditions present in adult human brain.
“signifies that our results in both the HeLa model system and primary cultured neuronsative of the conditions present in adult human brain.”
Quote in the paperSubstantial claim- Rests on an assumption: Intactness of the trimeric complex in postmortem human brain tissue indicates that the complex is functional in adult human brain.
- Interpretationown data
The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms.
“The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms.”
Quote in the paperSubstantial claim- Rests on an assumption: Loss or pharmacological inhibition of TMEM97 and/or PGRMC1 disrupts the TMEM97/PGRMC1/LDLR complex.
- Interpretationown data
TMEM97 and PGRMC1 play a role in neuronal Aβ42 and apoE-associated Aβ42 uptake.
“The results highlight the role of TMEM97 and PGRMC1 in neuronal Aβ42 and apoE-associated Aβ42 uptake”
Quote in the paperSubstantial claim - Interpretationown data
The three proteins TMEM97, PGRMC1, and LDLR form a trimeric complex in primary neurons.
“Taken together, these data indicate that the three proteins form a trimeric complex in primary neurons.”
Quote in the paperSubstantial claim - Interpretationown data
TMEM97 and PGRMC1 are therapeutic targets for inhibition of Aβ42 and apoE uptake.
“we provide strong experimental evidence that TMEM97 and PGRMC1 are therapeutic targets for inhibition of Aβ42 and apoE uptake.”
Quote in the paperSubstantial claim - Study design and conductown data
Dot blot analysis indicated that only oAβ42 showed positive reactivity to the oligomer-specific A11 antibody, indicating pure samples of the three aggregation states.
“Dot blot analysis indicated positive reactivity for all samples with Aβ42 6E10 antibody, which recognizes all species of Aβ42, however only oAβ42 showed positive reactivity to the oligomer specific A11 antibody, indicating pure samples of the three aggregation states (SI Appendix, Fig. S1B).”
Quote in the paperSubstantial claim - Study design and conductcitation
The TMEM97 KO, PGRMC1 KO, and DKO HeLa cell lines had complete ablation of TMEM97 and/or PGRMC1.
“previous studies characterized these cell lines and western blot data demonstrated a complete ablation of TMEM97 and/or PGRMC1 in the knockout cells [8, 39].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, Metz T, Carlin S et al (2018) Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 8:16845. https://doi.org/10.1038/s41598-018-35430-3 source
A check is scheduled.
- cites [39] Zeng C, Weng CC, Schneider ME Jr, Puentes L, Riad A, Xu K, Makvandi M, Jin L et al (2019) TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell Death Discov 5:58. https://doi.org/10.1038/s41420-019-0141-2 source
A check is scheduled.
- Premisecitation
Disrupting the TMEM97/PGRMC1/LDLR complex by genetically ablating or pharmacologically targeting TMEM97 or PGRMC1 decreases LDL internalization.
“We found that disrupting this complex by genetically ablating or by pharmacologically targeting TMEM97 or PGRMC1 resulted in a decreased capacity for LDL internalization.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, Metz T, Carlin S et al (2018) Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 8:16845. https://doi.org/10.1038/s41598-018-35430-3 source
- Interpretationreasoning
The TMEM97-PGRMC1-LDLR complex is an attractive target to inhibit Aβ42 uptake in neuronal cells primarily, where accumulation and aggregation causes the deleterious neurotoxic effects that promote pathogenesis of AD.
“This observation renders this complex as an attractive target to inhibit Aβ42 uptake in neuronal cells primarily, where accumulation and aggregation causes the deleterious neurotoxic effects that promote pathogenesis of AD.”
Quote in the paperSubstantial claim - Interpretationreasoning
The TMEM97-PGRMC1-LDLR trimeric complex has therapeutic potential as a target for reducing Aβ42 accumulation in neurons.
“reinforces the therapeutic potential of the TMEM97-PGRMC1-LDLR trimeric complex as a target for reducing Aβ42 accumulation in neurons.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 16
- It may state two separate claims as one. 12
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNeuronal dysfunction that led to memory impairment also caused pathological changes in neighboring cells.
“the observation that the neuronal dysfunction that led to memory impairment also caused pathological changes in neighboring cells [25, 48].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [25] Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R (2010) Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 13:190–196. https://doi.org/10.1038/nn.2476 source
The Abstract and Results report that Aβ overproduction in neurons reduced spine density and plasticity at nearby dendrites in rat hippocampal slices. The paper links Aβ to memory deficits as background, but it did not show that the neurons causing the nearby changes also led to memory impairment. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [48] Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, Roher AE, Walker LC (2000) Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice. J Neurosci 20:3606–3611 source
The Results (page unavailable) report that extract-injected mice did not differ significantly from controls in the water maze and showed no behavioral dysfunction. The paper attributes the observed amyloid deposits to infusion of Alzheimer brain extract, not to memory-impairing neuronal dysfunction causing changes in neighboring cells. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe apoE4 allele is the greatest risk factor associated with development of AD.
“Due to the apoE4 allele being the greatest risk factor associated with development of AD”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [42] Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. https://doi.org/10.1038/nrneurol.2012.263 source
The section “APOE ε4 as a strong risk factor for AD” calls ε4 the strongest genetic risk factor for AD and links it to increased risk of developing the disease. The claim omits “genetic,” so the source does not establish that ε4 is the greatest risk factor overall. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [43] Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–339. https://doi.org/10.1016/j.cell.2019.09.001 source
The ApoE section says APOE is the strongest genetic risk factor for late-onset Alzheimer disease (LOAD) and that one or two copies of the ε4 allele increase LOAD risk. The claim omits both the genetic-risk and late-onset qualifiers, describing ε4 as the greatest risk factor for AD generally. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [44] Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R, Huang DY, Pericak-Vance M et al (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A 91:11183–11186. https://doi.org/10.1073/pnas.91.23.11183 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGlial cells such as astrocytes and microglia play a role in Aβ42 clearance by mechanisms including proteolytic degradation of endocytosed proteins, clearance through the blood brain barrier, and clearance to the CSF via the glymphatic pathway.
“Glial cells such as astrocytes and microglia also play a role in Aβ42 clearance by several mechanisms including proteolytic degradation of endocytosed proteins, clearance through the blood brain barrier, and clearance from to the CSF via the glymphatic pathway [46].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [46] Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H et al (2015) Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11:457–470. https://doi.org/10.1038/nrneurol.2015.119 source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataFluorescent fAβ42 was not internalized by cells but accumulated on the cell surface.
“Interestingly fluorescent fAβ42 was not internalized by the cells, but accumulated on the cell surface (Fig 2B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe AD tissue section displayed positive staining for Aβ, whereas normal human tissue sections did not show a signal with an Aβ antibody.
“The AD tissue section displayed positive staining for Aβ whereas the normal human tissue sections did not show a signal in immunofluorescent staining with an Aβ antibody (SI Appendix, Fig. S4).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTreatment of Scramble/Cas9 cells with 500 nM RHM-4, SW43, or AG-205 significantly reduced internalization of mAβ42 and oAβ42 alone or complexed with apoE3, and to a lesser extent reduced cell-associated fAβ42 alone or complexed with apoE3.
“Scramble/Cas9 cells when treated with 500 nM RHM-4, SW43, or AG-205 showed significantly reduced capacity for internalizing mAβ42 and oAβ42 alone or when complexed with apoE3; and to a lesser extent reduced the cell associated fAβ42 alone or when complexed with apoE3 (Fig. 1C).”
Quote in the paperSubstantial claimProbably not a substantial claim. It may be too vague to check against evidence.
InterpretationreasoningDeveloping compounds that target the TMEM97/PGRMC1/LDLR complex may represent a novel strategy in delaying the clinical progression of AD.
“Thus, developing compounds that target the TMEM97/PGRMC1/LDLR complex may represent a novel strategy in delaying the clinical progression of AD.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationoAβ42 has been detected within neuronal exosomes.
“oAβ42 has been detected within neuronal exosomes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Sardar Sinha M, Ansell-Schultz A, Civitelli L, Hildesjo C, Larsson M, Lannfelt L, Ingelsson M, Hallbeck M (2018) Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol 136:41–56. https://doi.org/10.1007/s00401-018-1868-1 source
Probably not a substantial claim.
InterpretationreasoningModulation of intercellular and extracellular Aβ42 pools may have a positive influence on clearance by keeping Aβ42 in the extracellular space where it may be readily available for proteolytic degradation or clearance to the CSF.
“The modulation of intercellular and extracellular Aβ42 pools may have a positive influence on clearance by keeping Aβ42 in the extracellular space where it may be readily available for proteolytic degradation or clearance to the CSF.”
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.
PremisecitationApoE interacts with Aβ42, affects its clearance from the CNS, and increases deposition into plaques.
“ApoE has been shown to interact with Aβ42 and affect its clearance from the CNS, and increasing deposition into plaques [29].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135:235–238. https://doi.org/10.1016/0304-3940(92)90444-c source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe ROUT method (Q = 1%) verified that there were no outliers in any of the datasets.
“The ROUT method (Q = 1%) was used to verify that there were no outliers in any of the datasets.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationWithin the CNS, apoE transports cholesterol to neurons via recognition by the LDLR family including LDLR and LRP receptors.
“Within the CNS, apoE is primarily produced by astrocytes and transports cholesterol to neurons via its recognition by the LDLR family including LDLR and LDLR-related protein (LRP) receptors [27].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Bu G (2009) Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344. https://doi.org/10.1038/nrn2620 source
It may state two separate claims as one.
InterpretationreasoningTMEM97 and PGRMC1 may be novel therapeutic targets for inhibiting neuronal uptake of Aβ42 and ApoE-associated Aβ42 and potentially reduce Aβ-associated neurotoxicity.
“the results from this study reveal that TMEM97 and PGRMC1 may be novel therapeutic target for inhibiting neuronal uptake of Aβ42 and ApoE-associated Aβ42 and potentially reduce Aβ-associated neurotoxicity.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premiseown dataA trimeric protein complex formed between LDLR, TMEM97, and PGRMC1 is important for efficient uptake of LDL in cancer cells.
“In our previous study, we described a trimeric protein complex formed between LDLR, TMEM97, and PGRMC1, and that this intact complex is important for efficient uptake of LDL in cancer cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationIncreased uptake of neurotoxic Aβ42 peptides results in accumulation and aggregation within neurons, eventually leading to formation of plaques and neuronal death.
“Evidence suggests that increased uptake of these neurotoxic Aβ42 peptides results in accumulation and aggregation within neurons eventually leading the formation of plaques and neuronal death [40, 41].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [40] Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884 source
- cites [41] Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95:6448–6453. https://doi.org/10.1073/pnas.95.11.6448 source
Probably not a substantial claim.
InterpretationreasoningReducing neuronal uptake of Aβ42 may slow the cytotoxic effects of intracellular aggregation.
“Reducing neuronal uptake may slow the cytotoxic effects of intracellular aggregation.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLRP1 mediates neuronal Aβ42 uptake.
“As LRP1 has been previously shown to mediate neuronal Aβ42 uptake”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Fuentealba RA, Liu Q, Zhang J, Kanekiyo T, Hu X, Lee JM, LaDu MJ, Bu G (2010) Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PLoS One 5:e11884. https://doi.org/10.1371/journal.pone.0011884 source
It may state two separate claims as one.
Interpretationown dataThe binding of radiolabeled RHM-4 indicates the presence and high expression of TMEM97 in primary neurons.
“further indicating the presence and high expression of TMEM97 in the primary neurons.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationExosomes facilitated delivery of oAβ42 and induced toxic effects.
“Data from cells treated with these exosomes also revealed that the exosomes facilitated delivery of oAβ42 and induced toxic effects [24].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Sardar Sinha M, Ansell-Schultz A, Civitelli L, Hildesjo C, Larsson M, Lannfelt L, Ingelsson M, Hallbeck M (2018) Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol 136:41–56. https://doi.org/10.1007/s00401-018-1868-1 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe presence of one apoE4 allele increases AD risk 3-fold and two alleles increase risk 12-fold, while one or more apoE2 alleles reduce AD risk.
“The presence of one apoE4 allele results in a 3-fold increased risk for developing AD, while the presence of two alleles result in a 12-fold increased risk factor, while patients with one or more apoE2 alleles have a reduced risk for developing AD [28].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol 10:241–252. https://doi.org/10.1016/S1474-4422(10)70325-2 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationSeveral proposed mechanisms by which cell-to-cell transfer of Aβ42 occurs include exosomes and direct transmission of Aβ42 from neuron to neuron connected by tunneling nanotubes.
“There have been several proposed mechanisms by which this process occurs including exosomes and direct transmission of Aβ42 from neuron to neuron that are directly connected by tunneling nanotubes [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J Neurosci 32:8767–8777. https://doi.org/10.1523/JNEUROSCI.0615-12.2012 source
It may state two separate claims as one.
PremisecitationAβ42 aggregation also begins within neurons, where dysregulated uptake and lysosomal degradation lead to intraneuronal accumulation and aggregation.
“Although amyloid beta plaques are extracellular, mounting evidence suggests that aggregation also begins within neurons, where uptake and subsequent degradation within lysosomes has been dysregulated leading to intraneuronal accumulation leading to aggregation [14–20].”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [14] Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, Mehta PD, Buxbaum J et al (2004) Abeta localization in abnormal endosomes: Association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging 25:1263–1272. https://doi.org/10.1016/j.neurobiolaging.2004.02.027 source
- cites [15] D'Andrea MR, Nagele RG, Wang HY, Peterson PA, Lee DH (2001) Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology 38:120–134. https://doi.org/10.1046/j.1365-2559.2001.01082.x source
- cites [16] Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20. https://doi.org/10.1016/s0002-9440(10)64700-1 source
- cites [17] McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 46:860–866. https://doi.org/10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m source
- cites [18] Friedrich RP, Tepper K, Ronicke R, Soom M, Westermann M, Reymann K, Kaether C, Fandrich M (2010) Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A 107:1942–1947. https://doi.org/10.1073/pnas.0904532106 source
- cites [19] Hu X, Crick SL, Bu G, Frieden C, Pappu RV, Lee JM (2009) Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc Natl Acad Sci U S A 106:20324–20329. https://doi.org/10.1073/pnas.0911281106 source
- cites [20] Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E (2010) Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathol 119:523–541. https://doi.org/10.1007/s00401-010-0679-9 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe primary rat cortical neurons used were mature DIV 21 neurons, evident by their morphology and expression of MAP2.
“For these studies we used mature DIV 21 primary rat cortical neurons, evident by their morphology and expression of MAP2 (Fig 3A).”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Loss or pharmacological inhibition of TMEM97 and/or PGRMC1 disrupts the TMEM97/PGRMC1/LDLR complex.
“The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons.”
The paper relies on this without support.
Intactness of the trimeric complex in postmortem human brain tissue indicates that the complex is functional in adult human brain.
“We observed that the trimeric complex is intact in both human tissue samples, and signifies that our results in both the HeLa model system and primary cultured neuronsative of the conditions present in adult human brain.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Knockout of TMEM97 or PGRMC1 did not alter the uptake of radiolabeled somatostatin or insulin, indicating a specific role of S2R regulation of trafficking through LDLR.
“Further, to understand whether S2R alters all clathrin-mediated endocytic pathways or just the update of LDL, radiolabeled [125I]TYR11-somatostatin and [125I] insulin uptake was assessed, but knockout of TMEM97 or PGRMC1 did not alter the uptake of either substrate, indicating a specific role of S2R regulation of trafficking through LDLR [62].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [62]
The TMEM97/PGRMC1/LDLR triad is responsible for the uptake of amyloid-β oligomers and apolipoprotein E into neurons; knockdown of TMEM97 or modulation of TMEM97 with S2R ligands RHM-4 and SW43 substantially decreased the uptake of both amyloid-β oligomers and apolipoprotein E, but apolipoprotein E was not required for amyloid-β oligomer uptake.
“The TMEM97/PGRMC1/LDLR triad is responsible for the uptake of amyloid-β oligomers and apolipoprotein E into neurons, as knockdown of TMEM97 or modulation of TMEM97 with S2R ligands including RHM-4 and SW43 substantially decreased the uptake of both amyloid-β oligomers and apolipoprotein E, but apolipoprotein E was not required for amyloid-β oligomer uptake [62].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [62]
The TMEM97/PGRMC1/LDLR complex may control the internalization of monomers and oligomers of Aβ.
“Linking this function to Alzheimer’s, in cellular models, TMEM97 has recently been shown to form a ternary complex with Progesterone receptor membrane component 1 (PGRMC1) and LDLR [55] that may control the internalization of monomers and oligomers of Aβ [54].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [54]
In cellular models, treatment with modulators or knocking out Sigma-2 receptor (S2R) constituents TMEM97 or the co-receptor PGRMC1 reduces the internalization of Aβ.
“More specifically, in cellular models, treatment with modulators or knocking out Sigma-2 receptor (S2R) constituents TMEM97 or the co-receptor PGRMC1 reduces the internalization of Aβ [27, 54].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [54]
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.
List of three apoE isoforms repeats E4 and omits E3
MinorThe paper identifies the three tested isoforms as apoE2, apoE3, and apoE4, but this list of all three gives E2, E4, and E4.
“all three isoforms (E2, E4, E4)”
“the apoE isoforms, apoE2, apoE3, and apoE4”
Oligomer solution is described as diluted to a higher concentration
MinorThe peptide is described as being at 5 μM in DMSO and then diluted to 100 μM. Dilution cannot raise its concentration from 5 μM to 100 μM.
“An aliquot of HFIP-treated peptide was dissolved in anhydrous DMSO (5 μM)”
“and diluted to 100 μM in serum-free and phenol red-free cell culture media”
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Synaptic degeneration in Alzheimer disease
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BindingDB Entry 50018852: Development of Fluorescent 4-[4-(3
BindingDB (2024) · UC San Diego · doi:10.7270/q2125xwb
BindingDB Entry 50019660: Targeting σ
BindingDB (2024) · UC San Diego · doi:10.7270/q2f76hxn
Metadata
- Authors
- Riad, A., Lengyel-Zhand, Z., Zeng, C., Weng, C.-C., Lee, V. M.-Y., Trojanowski, J. Q., & Mach, R. H.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Mach, Robert H.
- Venue
- Molecular Neurobiology
- Published
- 2020-06-23
- Volume
- 57
- Issue
- 9
- Pages
- 3803-3813
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC7415709
- OpenAlex
- W3036273457
- Cited by
- 81
- References
- 49
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 15 · 2023: 15 · 2022: 15 · 2021: 11 · 2020: 3
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Molecular Neurobiology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (2T32DA028874-08)
- Michael J. Fox Foundation for Parkinson's Research (Ref: 14638.01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sigma-2 receptor, TMEM97, PGRMC1, LDL receptor, amyloid-beta 42, amyloid-beta oligomers, apolipoprotein E, receptor complex, cellular uptake, Alzheimer's disease, neuronal uptake, receptor internalization, therapeutic target
- MeSH terms
- Adult, Animals, Apolipoproteins E, Cell Line, Cells, Cultured, Cerebral Cortex, Humans, Membrane Proteins, Neurons, Peptide Fragments, Receptors, LDL, Receptors, Progesterone, Amyloid beta-Peptides, Rats, Protein Aggregates
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