Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease

Probably not a substantial claim.

TMEM97 was recently identified as the gene that codes for the Sigma-2 receptor.

“TMEM97 was recently identified as the gene that codes for the Sigma-2 receptor [3].”

• cites [3] Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC (2017) Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci USA 114:7160–7165. https://doi.org/10.1073/pnas.1705154114 sourceSupported

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Other suggested Aβ binding partners at synapses include the α7-nicotinic receptor, Ephrin A4, PSD95 and LilrB2.

“Other suggested Aβ binding partners at synapses include the α7-nicotinic receptor [49], Ephrin A4 [73], PSD95 [35, 50, 52] and LilrB2 [32].”

• cites [49] Parri HR, Hernandez CM, Dineley KT (2011) Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82:931–942. https://doi.org/10.1016/j.bcp.2011.06.039 sourceCheck pending
• cites [73] Vargas LM, Leal N, Estrada LD, González A, Serrano F, Araya K et al (2014) EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PLoS ONE 9:e92309. https://doi.org/10.1371/journal.pone.0092309 sourceCheck pending
• cites [35] Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL et al (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200. https://doi.org/10.1523/JNEUROSCI.3432-04.2004 sourcePartly supported

  In “Clusters of ADDL binding sites are coincident with synapses” (page unavailable), the paper reports that Aβ oligomer binding sites colocalize with PSD-95 at synapses. It treats PSD-95 as a synaptic marker, not an established Aβ binding partner; the Discussion (page unavailable) says the identity of the binding sites remains unknown. The citation is attached to PSD-95, so the other proteins in the sentence are not assessed here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [50] Pham E, Crews L, Ubhi K, Hansen L, Adame A, Cartier A et al (2010) Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 277:3051–3067. https://doi.org/10.1111/j.1742-4658.2010.07719.x sourceCheck pending
• cites [52] Pickett EK, Koffie RM, Wegmann S, Henstridge CM, Herrmann AG, Colom-Cadena M et al (2016) Non-fibrillar oligomeric amyloid-β within synapses. J Alzheimers Dis 53:787–800. https://doi.org/10.3233/JAD-160007 sourceCheck pending

Probably not a substantial claim.

Sigma-2 modulators including CT1812 can improve cognitive deficits in a mouse model of Alzheimer's.

“In the context of Alzheimer’s, in 2014, Izzo and colleagues found that Sigma-2 modulators including CT1812 could displace Aβ synthetic oligomers from their synaptic receptors in cellular models and could improve cognitive deficits in a mouse model of Alzheimer’s [27].”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourcePartly supported

  The Results sections on neuronal binding and in vivo efficacy report that sigma-2/PGRMC1-targeting compounds displaced synthetic Aβ oligomers from neuronal cultures and improved memory deficits in transgenic Alzheimer’s-model mice. The compounds named for these findings include CT0093, CT0109, CT01344 and CT01346; our copy does not identify CT1812 as one of them. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

The most studied binding partner of Aβ is PrPc, which through a cascade involving a complex with mGluR5 may lead to toxicity independently or via tau.

“The most studied binding partner is the PrPc, which through a cascade involving a complex with mGluR5 may lead to toxicity independently or via tau [37, 62, 72, 79].”

• cites [37] Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457:1128–1132. https://doi.org/10.1038/nature07761 sourcePartly supported

  The paper reports that PrPC binds Aβ42 oligomers and is required for their inhibition of hippocampal long-term potentiation (Abstract; page not specified). It proposes a downstream signaling cascade and a putative co-receptor, but does not identify mGluR5 or describe a tau-dependent or tau-independent route. It also does not establish that PrPC is the most studied Aβ binding partner. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [62] Smith LM, Kostylev MA, Lee S, Strittmatter SM (2019) Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem 294:6042–6053. https://doi.org/10.1074/jbc.RA118.006252 sourceCheck pending
• cites [72] Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79:887–902. https://doi.org/10.1016/j.neuron.2013.06.036 sourcePartly supported

  The Introduction and Discussion identify PrPC as an Aβ oligomer binding partner and report that the Aβo–PrPC–mGluR5 complex contributes to dendritic spine loss and impaired neuronal function. The Discussion notes that Fyn binds Tau but presents implications beyond glutamate-receptor dysregulation as a possibility, not an established route to toxicity. The paper also does not establish that PrPC is the most studied Aβ binding partner. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Izzo and colleagues found an improvement of cognition in mice exhibiting more than 80% estimated receptor occupancy.

“Izzo and colleagues found an improvement of cognition in mice exhibiting more than 80% estimated receptor occupancy”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceSupported

Probably not a substantial claim.

Aβ oligomers have been shown to bind saturably to a single site, suggesting specific pharmacological interactions with receptors.

“Further, while Aβ fibrils bind non-specifically to a variety of surfaces, and Aβ monomers bind to several receptors when applied exogenously [5], Aβ oligomers have been shown to bind saturably to a single site[27, 62] suggesting specific pharmacological interactions with receptors.”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceSupported
• cites [62] Smith LM, Kostylev MA, Lee S, Strittmatter SM (2019) Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem 294:6042–6053. https://doi.org/10.1074/jbc.RA118.006252 sourceNot checked yet

It may state two separate claims as one.

The density of TMEM97 objects was significantly higher in Alzheimer's than control cases (fold increase: 1.56; effect of disease F[1,19.36] = 4.41, p = 0.049, no significant sex differences).

“The density of TMEM97 objects was significantly higher in Alzheimer’s than control cases (fold increase: 1.56; effect of disease F[1,19.36] = 4.41, p = 0.049, no significant sex differences).”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Body weight was different between male and female mice with males being heavier (F[1, 36] = 62.33, p < 0.0001).

“Body weight, which could affect drug uptake, did not differ between treatment groups (F[1, 36] = 0.74, p = 0.40), but body weight was different between male and female mice with males being heavier (F[1, 36] = 62.33, p < 0.0001).”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

There was no treatment:sex interaction in analysis of body weight nor a significant difference in the numbers of male vs female mice in the different treatment groups (Fisher test p = 1, 95% CI = 0.30, 5.04).

“There was no treatment:sex interaction in analysis of body weight nor was there a significant difference in the numbers of male vs female mice in the different treatment groups (Fisher test p = 1, 95% CI = 0.30, 5.04).”

It may state two separate claims as one.

Pre-incubation with homogenate for 24 h before CT1812 or vehicle treatment induced a significant interaction between Aβ status of the homogenate and drug treatment (F[1,257] = 9.06, p = 0.003) with a significant decrease in peak frequency between Aβ-incubation followed by vehicle treatment and Aβ + followed by CT1812 treatment.

“Pre-incubation with homogenate for 24 h before CT1812 or vehicle treatment induced a significant interaction between Aβ status of the homogenate and drug treatment (F[1,257] = 9.06, p = 0.003) with a significant decrease in peak frequency between Aβ–incubation followed by vehicle treatment and Aβ + followed by CT1812 treatment.”

It may state two separate claims as one.

CT1812 did not statistically significantly influence the overall densities of Aβ, TMEM97 or PSD95 nor the synaptic localization of Aβ and/or TMEM97.

“CT1812 did not statistically significantly influence the overall densities of Aβ, TMEM97 or PSD95 nor the synaptic localization of Aβ and/or TMEM97 (Fig. 4A,C,E).”

It may state two separate claims as one.

With our technique, we do not observe somatic labelling of PSD95, rather we observe discrete puncta that are opposed to presynaptic terminal labelling.

“There will be synaptic protein in cell bodies of neurons where they are produced before transport to synapses; however, with our technique, we do not observe somatic labelling of PSD95, rather we observe discrete puncta that are opposed to presynaptic terminal labelling [12].”

• cites [12] Colom-Cadena M, Davies C, Sirisi S, Lee J-E, Simzer EM, Tzioras M et al (2023) Synaptic oligomeric tau in Alzheimer’s disease—a potential culprit in the spread of tau pathology through the brain. Neuron 111:2170-2183.e6. https://doi.org/10.1016/j.neuron.2023.04.020 sourceCheck pending

• AssumptionRests on an assumption: There will be synaptic protein in cell bodies of neurons where they are produced before transport to synapses.

It may state two separate claims as one.

Male APP/PS1 + Tau mice had an average of 85.13 ± 6.4% estimated receptor occupancy, while females had an average of 69.69 ± 11% (β = 15.44; p < 0.001).

“Male APP/PS1 + Tau mice had an average of 85.13 ± 6.4% estimated receptor occupancy, while females had an average of 69.69 ± 11% (β = 15.44; p < 0.001, Fig. 4B).”

It may state two separate claims as one.

Treatment of the Alzheimer's mouse model with TMEM97 modulators did not result in a recovery of synaptic densities nor a decrease of Aβ synaptic localization.

“the treatment of the Alzheimer’s mouse model with TMEM97 modulators did not result in a recovery of synaptic densities nor a decrease of Aβ synaptic localization”

It may state two separate claims as one.

STRING protein interaction analysis of Aβ + Drug vs. Aβ + Vehicle conditions (unadjusted p < 0.05) confirmed the findings of TMEM97 localization to synapses. The top 8 GO Components (sorted by strength) were involved in synaptic biology.

“STRING (Version 11.5) protein interaction analysis of Aβ + Drug vs. Aβ + Vehicle conditions (unadjusted p value < 0.05) confirmed the findings of TMEM97 localization to synapses. The top 8 GO Components (sorted by strength) were involved in synaptic biology (Fig. 5G).”

It may state two separate claims as one.

In post synapses, FRET was observed between Aβ and PrPc, between TMEM97 and PGRMC1, and between TMEM97 and PrPc.

“In post synapses, we also observed FRET between Aβ and PrPc—which has also been observed to bind Aβ in model systems[62]—and between TMEM97 and PGRMC1 which are known to be binding partners in vitro and in human cases [55], and between TMEM97 and PrPc (Fig. 3).”

• cites [62] Smith LM, Kostylev MA, Lee S, Strittmatter SM (2019) Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem 294:6042–6053. https://doi.org/10.1074/jbc.RA118.006252 sourceCheck pending
• cites [55] Riad A, Zeng C, Weng C-C, Winters H, Xu K, Makvandi M 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 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

There were no sex effects in the proportion of synapses containing TMEM97.

“There were no sex effects in the proportion of synapses containing TMEM97.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Neurons were active in all conditions.

“Images of GCaMP6 fluorescence show that neurons were active in all conditions.”

It may state two separate claims as one.

The difference between Aβ− and Aβ + homogenate was much smaller with only 7 differentially expressed genes (adjusted p value < 0.05), 3 upregulated and 4 downregulated.

“The difference between Aβ− and Aβ + homogenate was much smaller with only 7 differentially expressed genes (adjusted p value < 0.05), 3 upregulated and 4 downregulated (Fig. 5D).”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Several of the transcripts regulated by CT1812 are expressed in astrocytes, which are observed in small numbers in our cultures (averaging 16% GFAP positive cells in the 200 day old cultures used).

“Several of the transcripts regulated by CT1812 are expressed in astrocytes, which are observed in small numbers in our cultures (averaging 16% GFAP positive cells in the 200 day old cultures used, Fig. 5F).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Post-synaptic terminal density was reduced in AD (7% reduction in PSD density F[1,28.73] = 4.36, p = 0.046, no significant sex differences).

“As previously described [34], post-synaptic terminal density was reduced in AD (Fig. 1B, 7% reduction in PSD density F[1,28.73] = 4.36, p = 0.046, no significant sex differences).”

• cites [34] Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A, Joyner D et al (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–2168. https://doi.org/10.1093/brain/aws127 sourceNot checked — no full text of the source

It may state two separate claims as one.

CT1812 treatment in transgenic mice did not change plaque burdens but did reduce astrogliosis in hippocampus.

“CT1812 treatment in transgenic mice did not change plaque burdens but did reduce astrogliosis in hippocampus (Supplementary Fig S4).”

It may state two separate claims as one.

FRET experiments confirm close proximity within synapses of Aβ and TMEM97, Aβ and PrPc, TMEM97 and PrPc, TMEM97 and PGRMC1 and Aβ and PSD95, but not PSD95 and synaptophysin or PSD95 and PGRMC1.

“In summary, our FRET experiments confirm close proximity within synapses of Aβ and TMEM97, Aβ and PrPc, TMEM97 and PrPc, TMEM97 and PGRMC1 and Aβ and PSD95, but not PSD95 and synaptophysin or PSD95 and PGRMC1, which are robust as both technical and biological negative controls do not show FRET signal.”

It may state two separate claims as one.

There was a significant interaction between disease and sex in the proportion of synapses with Aβ (disease*sex interaction F[1,21.86] = 5.1, p = 0.034) with female subjects having more synaptic Aβ.

“Interestingly, there was a significant interaction between disease and sex in the proportion of synapses with Aβ (disease* sex interaction F[1,21.86] = 5.1, p = 0.034) with female subjects having more synaptic Aβ.”

It may state two separate claims as one.

Both human brain homogenate treated groups are lower than the control (vehicle treatment; p < 0.0001), indicating that exposure to human brain homogenate affects cell function.

“However, both human brain homogenate treated groups are lower than the control (vehicle treatment; Tukey-corrected post-hoc test after linear mixed effects model, p < 0.0001) indicating that exposure to human brain homogenate affects cell function.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In the cultures studied, ~16% of cells were GFAP+ astrocytes.

“In the cultures studied, ~ 16% of cells were GFAP + astrocytes”

It may state two separate claims as one.

The top gene ontology terms important are synaptic and include post-synaptic density and post-synaptic membrane.

“the top gene ontology terms important are synaptic and include post-synaptic density and post-synaptic membrane”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Sigma-2 receptor ligands prevent neurodegeneration in a worm model expressing human amyloid precursor protein.

“Yi et al.and Mondal et al.similarly found that Sigma-2 receptor ligands prevent neurodegeneration in a worm model expressing human amyloid precursor protein [44, 77].”

• cites [44] Mondal S, Hegarty E, Sahn JJ, Scott LL, Gökçe SK, Martin C et al (2018) High-content microfluidic screening platform used to identify σ2R/Tmem97 binding ligands that reduce age-dependent neurodegeneration in C. elegans SC_APP model. ACS Chem Neurosci 9:1014–1026. https://doi.org/10.1021/acschemneuro.7b00428 sourceCheck pending
• cites [77] Yi B, Sahn JJ, Ardestani PM, Evans AK, Scott L, Chan JZ et al (2017) Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuro-inflammation in experimental models of Alzheimer’s disease. J Neurochem 140:561–575. https://doi.org/10.1111/jnc.13917 sourceCheck pending

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Changes in non-neuronal cells are important in Alzheimer's disease pathogenesis.

“While it is clear that toxicity of tau and changes in non-neuronal cells are also important in disease pathogenesis [24], substantial evidence supports an important role for Aβ in synaptotoxicity early in the disease process in Alzheimer’s [38].”

• cites [24] Henstridge CM, Hyman BT, Spires-Jones TL (2019) Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat Rev Neurosci 20:94–108. https://doi.org/10.1038/s41583-018-0113-1 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Sigma-2 receptors have been studied for more than four decades and are drug targets for several conditions including cancer, pain and diverse CNS disorders.

“Sigma-2 receptors have been studied for more than four decades and are drug targets for several conditions including cancer, pain and diverse CNS disorders [22, 58]; and most notably, a Sigma-2 modulator, CT1812, is in clinical development in Phase 2 trials for Alzheimer’s disease and dementia with Lewy bodies [11, 21].”

• cites [22] Guo L, Zhen X (2015) Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem 22:989–1003. https://doi.org/10.2174/0929867322666150114163607 sourceNot checked — no full text of the source
• cites [58] Schmidt HR, Kruse AC (2019) The molecular function of σ receptors: past, present, and future. Trends Pharmacol Sci 40:636–654. https://doi.org/10.1016/j.tips.2019.07.006 sourceCheck pending

Probably not a substantial claim. It may state two separate claims as one.

The study of synapses in the human brain represents a technical challenge due to their small volumes, which are smaller than the diffraction limit of light microscopy, making colocalization studies difficult.

“The study of synapses in the human brain represents a technical challenge due to their small volumes, which are smaller than the diffraction limit of light microscopy, making colocalization studies difficult.”

Probably not a substantial claim.

Synaptic Aβ binding partners have been identified in cell culture systems and mouse models.

“Synaptic Aβ binding partners have been identified in cell culture systems and mouse models, but their human relevance is still debated (reviewed in [5, 30, 46, 63]).”

• cites [5] Benilova I, De Strooper B (2013) Promiscuous Alzheimer’s amyloid: yet another partner. Science 341:1354–1355. https://doi.org/10.1126/science.1244166 sourceNot checked — no full text of the source
• cites [30] Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM (2016) Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem 291:3174–3183. https://doi.org/10.1074/jbc.R115.702704 sourceNot checked yet
• cites [46] Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P (2018) Cellular receptors of amyloid β oligomers (AβOs) in Alzheimer’s disease. Int J Mol Sci 19:1884. https://doi.org/10.3390/ijms19071884 sourceNot checked yet
• cites [63] Smith LM, Strittmatter SM (2017) Binding sites for amyloid-β oligomers and synaptic toxicity. Cold Spring Harb Perspect Med 7:a024075. https://doi.org/10.1101/cshperspect.a024075 sourceCheck pending

Probably not a substantial claim.

Sigma-2 modulators including CT1812 can displace Aβ synthetic oligomers from their synaptic receptors in cellular models.

“In the context of Alzheimer’s, in 2014, Izzo and colleagues found that Sigma-2 modulators including CT1812 could displace Aβ synthetic oligomers from their synaptic receptors in cellular models and could improve cognitive deficits in a mouse model of Alzheimer’s [27].”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

TMEM97 is believed to be a key player of cholesterol homeostasis.

“TMEM97, initially known as MAC30 [47], is overexpressed in some cancers and it is believed to be a key player of cholesterol homeostasis [78] and calcium regulation [8, 74, 77].”

• cites [78] Zeng C, Weng C-C, Schneider ME, Puentes L, Riad A, Xu K et al (2019) TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell Death Discovery 5:1–12. https://doi.org/10.1038/s41420-019-0141-2 sourceCheck pending

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Toxicity of tau is important in Alzheimer's disease pathogenesis.

“While it is clear that toxicity of tau and changes in non-neuronal cells are also important in disease pathogenesis [24], substantial evidence supports an important role for Aβ in synaptotoxicity early in the disease process in Alzheimer’s [38].”

• cites [24] Henstridge CM, Hyman BT, Spires-Jones TL (2019) Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat Rev Neurosci 20:94–108. https://doi.org/10.1038/s41583-018-0113-1 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Cellular prion protein (PrPc) is the most studied Aβ binding candidate at synapses, either alone or through a complex with mGluR5.

“Among the Aβ binding candidates, cellular prion protein (PrPc) represents the most studied, either alone or through a complex with mGluR5 [37, 62, 72, 79].”

• cites [37] Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457:1128–1132. https://doi.org/10.1038/nature07761 sourceNot checked yet
• cites [62] Smith LM, Kostylev MA, Lee S, Strittmatter SM (2019) Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer’s disease relevance. J Biol Chem 294:6042–6053. https://doi.org/10.1074/jbc.RA118.006252 sourceCheck pending
• cites [72] Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79:887–902. https://doi.org/10.1016/j.neuron.2013.06.036 sourceNot checked yet
• cites [79] Zhang Y, Zhao Y, Zhang L, Yu W, Wang Y, Chang W (2019) Cellular prion protein as a receptor of toxic amyloid-β42 oligomers is important for Alzheimer’s disease. Front Cell Neurosci 13:339. https://doi.org/10.3389/fncel.2019.00339 sourceCheck pending

Probably not a substantial claim.

The human relevance of synaptic Aβ binding partners identified in cell culture systems and mouse models is still debated.

“Synaptic Aβ binding partners have been identified in cell culture systems and mouse models, but their human relevance is still debated (reviewed in [5, 30, 46, 63]).”

• cites [5] Benilova I, De Strooper B (2013) Promiscuous Alzheimer’s amyloid: yet another partner. Science 341:1354–1355. https://doi.org/10.1126/science.1244166 sourceNot checked — no full text of the source
• cites [30] Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM (2016) Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem 291:3174–3183. https://doi.org/10.1074/jbc.R115.702704 sourceNot checked yet
• cites [46] Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P (2018) Cellular receptors of amyloid β oligomers (AβOs) in Alzheimer’s disease. Int J Mol Sci 19:1884. https://doi.org/10.3390/ijms19071884 sourceNot checked yet
• cites [63] Smith LM, Strittmatter SM (2017) Binding sites for amyloid-β oligomers and synaptic toxicity. Cold Spring Harb Perspect Med 7:a024075. https://doi.org/10.1101/cshperspect.a024075 sourceCheck pending

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

In model systems, Aβ is often overexpressed or applied exogenously, and due to the 'sticky' nature of Aβ oligomers, this can result in false positive signals for interacting partners.

“Further, in model systems, Aβ is often overexpressed or applied exogenously, and due to the “sticky” nature of Aβ oligomers, this can result in false positive signals for interacting partners, which has been highlighted as a problem for translation in the field [5].”

• cites [5] Benilova I, De Strooper B (2013) Promiscuous Alzheimer’s amyloid: yet another partner. Science 341:1354–1355. https://doi.org/10.1126/science.1244166 sourceNot checked — no full text of the source

It may state two separate claims as one.

TMEM97 is a potential Aβ synaptic binding partner in human Alzheimer's disease brain, where it may mediate synaptotoxicity.

“These data support a role for transmembrane protein 97 in the synaptic binding of Aβ in human Alzheimer’s disease brain where it may mediate synaptotoxicity.”

• Also stated in: § Introduction · boosted

  “We demonstrate that TMEM97 is a potential Aβ synaptic binding partner in human brain tissue and confirms that Sigma-2 receptor complex allosteric modulator CT1812 can reduce interactions between TMEM97 and Aβ in vivo.”

It may state two separate claims as one.

Array tomography allows a 70nm axial resolution, which enables the identification of single synaptic terminals in three dimensions.

“Array tomography allows us to reach a 70nm axial resolution, which enables the identification of single synaptic terminals in three dimensions [31].”

• cites [31] Kay KR, Smith C, Wright AK, Serrano-Pozo A, Pooler AM, Koffie R et al (2013) Studying synapses in human brain with array tomography and electron microscopy. Nat Protoc 8:1366–1380. https://doi.org/10.1038/nprot.2013.078 sourceCheck pending

Probably not a substantial claim.

The mechanism(s) underlying synapse degeneration are still largely unknown.

“The mechanism(s) underlying synapse degeneration, however, are still largely unknown [10].”

• cites [10] Chen Y, Fu AKY, Ip NY (2019) Synaptic dysfunction in Alzheimer’s disease: mechanisms and therapeutic strategies. Pharmacol Ther 195:186–198. https://doi.org/10.1016/j.pharmthera.2018.11.006 sourceNot checked — no full text of the source

Probably not a substantial claim.

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].”

• cites [54] Riad A, Lengyel-Zhand Z, Zeng C, Weng C-C, Lee VM-Y, Trojanowski JQ et al (2020) The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates. Mol Neurobiol 57:3803–3813. https://doi.org/10.1007/s12035-020-01988-1 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

A Sigma-2 modulator, CT1812, is in clinical development in Phase 2 trials for Alzheimer's disease and dementia with Lewy bodies.

“Sigma-2 receptors have been studied for more than four decades and are drug targets for several conditions including cancer, pain and diverse CNS disorders [22, 58]; and most notably, a Sigma-2 modulator, CT1812, is in clinical development in Phase 2 trials for Alzheimer’s disease and dementia with Lewy bodies [11, 21].”

• cites [11] Cognition Therapeutics (2020) A Randomized, double-blind, placebo-controlled, parallel-group, phase 2 study to evaluate the safety and efficacy of CT1812 in subjects with mild to moderate Alzheimer’s disease. https://iadrp.nia.nih.gov/project/randomized-double-blind-placebo-controlled-parallel-group-phase-ii-study-evaluate-safety-1Not checked yet
• cites [21] Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ et al (2019) A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y) 5:20–26. https://doi.org/10.1016/j.trci.2018.11.001 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

TMEM97 is believed to be a key player of calcium regulation.

“TMEM97, initially known as MAC30 [47], is overexpressed in some cancers and it is believed to be a key player of cholesterol homeostasis [78] and calcium regulation [8, 74, 77].”

• cites [8] Cassano G, Gasparre G, Niso M, Contino M, Scalera V, Colabufo NA (2009) F281, synthetic agonist of the sigma-2 receptor, induces Ca2+ efflux from the endoplasmic reticulum and mitochondria in SK-N-SH cells. Cell Calcium 45:340–345. https://doi.org/10.1016/j.ceca.2008.12.005 sourceNot checked — no full text of the source
• cites [74] Vilner BJ, Bowen WD (2000) Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther 292:900–911 sourceNot checked — no full text of the source
• cites [77] Yi B, Sahn JJ, Ardestani PM, Evans AK, Scott L, Chan JZ et al (2017) Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuro-inflammation in experimental models of Alzheimer’s disease. J Neurochem 140:561–575. https://doi.org/10.1111/jnc.13917 sourceCheck pending

Probably not a substantial claim. It may state two separate claims as one.

Drug concentrations above 80% estimated receptor occupancy are effective and concentrations lower than 60% were ineffective.

“Since it has been reported that drug concentrations above 80% estimated receptor occupancy are effective and concentrations lower than 60% were ineffective [27], the effect on synaptic TMEM97 and Aβ localization was studied on the mice that reached an 80% estimated receptor occupancy threshold (n = 5 APP/PS1 + Tau mice, Table S1).”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The study of synaptic binding partners of Aβ yielded many candidates.

“The study of synaptic binding partners of Aβ yielded many candidates—reviewed in [30, 46, 63].”

• cites [30] Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM (2016) Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem 291:3174–3183. https://doi.org/10.1074/jbc.R115.702704 sourceNot checked yet
• cites [46] Mroczko B, Groblewska M, Litman-Zawadzka A, Kornhuber J, Lewczuk P (2018) Cellular receptors of amyloid β oligomers (AβOs) in Alzheimer’s disease. Int J Mol Sci 19:1884. https://doi.org/10.3390/ijms19071884 sourceNot checked yet
• cites [63] Smith LM, Strittmatter SM (2017) Binding sites for amyloid-β oligomers and synaptic toxicity. Cold Spring Harb Perspect Med 7:a024075. https://doi.org/10.1101/cshperspect.a024075 sourceCheck pending

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Laser and detector settings were maintained through the whole study avoiding major saturation.

“Laser and detector settings were maintained through the whole study avoiding major saturation, which is only applied in figures for image visualization purposes.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

With the current methodology, we cannot conclusively determine the proportion of Aβ bound to each potential receptor in synapses.

“With the current methodology, we cannot conclusively determine the proportion of Aβ bound to each potential receptor in synapses”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The linear mixed effects model including only diagnosis as a fixed effect and sample nested in case as a random effect was the best fit for the data as assessed with the Akaike Information Criteria (AIC).

“The linear mixed effects model including only diagnosis as a fixed effect and sample nested in case as a random effect was the best fit for the data as assessed with the Akaike Information Criteria (AIC) [9].”

• cites [9] Cavanaugh JE, Neath AA (2019) The Akaike information criterion: background, derivation, properties, application, interpretation, and refinements. WIREs Comput Stat 11:e1460. https://doi.org/10.1002/wics.1460 sourceNot checked — no full text of the source

It may state two separate claims as one.

The combination of array tomography with FRET enhances the lateral resolution to ~10 nm in the selected single synaptic terminals allowing us to determine whether proteins are close enough to be interacting.

“The combination of array tomography with FRET enhances the lateral resolution to ~ 10 nm in the selected single synaptic terminals allowing us to determine whether proteins are close enough to be interacting [23, 52].”

• cites [23] Hellenkamp B, Schmid S, Doroshenko O, Opanasyuk O, Kühnemuth R, Rezaei Adariani S et al (2018) Precision and accuracy of single-molecule FRET measurements-a multi-laboratory benchmark study. Nat Methods 15:669–676. https://doi.org/10.1038/s41592-018-0085-0 sourceCheck pending
• cites [52] Pickett EK, Koffie RM, Wegmann S, Henstridge CM, Herrmann AG, Colom-Cadena M et al (2016) Non-fibrillar oligomeric amyloid-β within synapses. J Alzheimers Dis 53:787–800. https://doi.org/10.3233/JAD-160007 sourceCheck pending

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Both Braak stage and Thal phase were higher in AD than control group due to the inclusion criteria for the groups (p < 0.01 Fisher's exact tests).

“Both Braak stage and Thal phase were higher in AD than control group due to our inclusion criteria for the groups (p < 0.01 Fisher’s exact tests).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The structural state of Aβ labelled with 6E10 antibody (monomer, oligomer or fibril) recognised in the present array tomography studies is not clear, which is a limitation of the study.

“The structural state of Aβ labelled with 6E10 antibody(monomer, oligomer or fibril) recognised in the present array tomography studies is not clear, which is a limitation of the study, but we have confirmed the interaction of TMEM7 with NAB61, an antibody that preferentially recognises fibrillar oligomers and reacts with synaptic oligomeric Aβ [34].”

• cites [34] Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A, Joyner D et al (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–2168. https://doi.org/10.1093/brain/aws127 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Mice of both sexes were randomised into vehicle or control groups.

“Mice of both sexes were randomised into vehicle or control groups.”

Probably not a substantial claim.

Within the limitations of the technique, we are able to observe proximity of synaptic proteins to a degree that has not previously been possible within human synapses.

“Within the limitations of the technique, we are able to observe proximity of synaptic proteins to a degree that has not previously been possible within human synapses.”

Probably not a substantial claim. It may state two separate claims as one.

CT1812 selectively displaces Aβ oligomers, but not monomer, from synaptic receptor sites and facilitates its clearance out of the brain.

“CT1812 has been previously demonstrated to selectively displace Aβ oligomers, but not monomer, from synaptic receptor sites and facilitate its clearance out of the brain [27]”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceNot checked yet

Probably not a substantial claim.

The 80% estimated receptor occupancy is the drug concentration threshold previously defined as effective.

“the drug concentration threshold previously defined as effective [27]”

• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceNot checked yet

Probably not a substantial claim.

Aβ can be found in synapses of Alzheimer's cases.

“It has been shown that Aβ can be found in synapses of Alzheimer’s cases [6, 29, 34, 51, 65, 66], but the mechanisms by which Aβ induces synaptic toxicity remain unclear.”

• cites [6] Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C et al (2016) Synaptic amyloid-β oligomers precede p-tau and differentiate high pathology control cases. Am J Pathol 186:185–198. https://doi.org/10.1016/j.ajpath.2015.09.018 sourceCheck pending
• cites [29] Jackson RJ, Rose J, Tulloch J, Henstridge C, Smith C, Spires-Jones TL (2019) Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers. Brain Commun 1:fcz003. https://doi.org/10.1093/braincomms/fcz003 sourceCheck pending
• cites [34] Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A, Joyner D et al (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–2168. https://doi.org/10.1093/brain/aws127 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Mice were randomly assigned to treatment groups and treated by blinded experimenters.

“Mice were randomly assigned to treatment groups and treated by blinded experimenters.”

It may state two separate claims as one.

TMEM97 (Sigma-2) has been previously linked to Alzheimer's, through in vitro and in vivo pharmacological modulation studies and with regard to a change in expression levels on synapses in Alzheimer's patients.

“TMEM97 (Sigma-2) has been previously linked to Alzheimer’s, through in vitro and in vivo pharmacological modulation studies and with regard to a change in expression levels on synapses in Alzheimer’s patients.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Due its hydrophobic nature, Aβ binds to lipid membranes interrupting membrane fluidity and destabilizing several membrane receptors.

“Due its hydrophobic nature, Aβ binds to lipid membranes interrupting membrane fluidity and destabilizing several membrane receptors [38].”

• cites [38] Li S, Selkoe DJ (2020) A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain. J Neurochem 154:583–597. https://doi.org/10.1111/jnc.15007 sourceNot checked yet

It may state two separate claims as one.

Modulating TMEM97 with CT1812 and modulating PrPc rescue cognition in plaque-bearing transgenic mice.

“both modulating TMEM97 with CT1812 and modulating PrPc rescue cognition in plaque-bearing transgenic mice [15, 27]”

• cites [15] Cox TO, Gunther EC, Brody AH, Chiasseu MT, Stoner A, Smith LM et al (2019) Anti-PrPC antibody rescues cognition and synapses in transgenic alzheimer mice. Ann Clin Transl Neurol 6:554–574. https://doi.org/10.1002/acn3.730 sourceCheck pending
• cites [27] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F 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 sourceNot checked yet

It may state two separate claims as one.

Including an interaction between sex and diagnosis was a better fit than without the interaction, and the final statistical model applied in the study was diagnosis*sex + (1|case/sample).

“Including an interaction between sex and diagnosis was a better fit than without the interaction, thus our final statistical model applied in the study was diagnosis*sex + (1|case/sample).”

Probably not a substantial claim.

For FRET analysis, donor-only (Cy3) and acceptor-only (Cy5) samples were imaged in each imaging session to calculate the donor-emission crosstalk with the acceptor emission (beta parameter) and the direct excitation of the acceptor by the donor excitation laser line (gamma parameter).

“For FRET analysis, donor-only (Cy3) and acceptor-only (Cy5) samples were imaged in each imaging session to calculate the donor-emission crosstalk with the acceptor emission (beta parameter) and the direct excitation of the acceptor by the donor excitation laser line (gamma parameter) [75, 80].”

• cites [75] Wouters FS, Verveer PJ, Bastiaens PI (2001) Imaging biochemistry inside cells. Trends Cell Biol 11:203–211. https://doi.org/10.1016/s0962-8924(01)01982-1 sourceNot checked — no full text of the source
• cites [80] Zimmermann T (2019) Photobleaching and sensitized emission-based methods for the detection of förster resonance energy transfer. Methods Mol Biol 2040:235–274. https://doi.org/10.1007/978-1-4939-9686-5_12 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

The synapse is believed to be the earliest affected structure in the context of Alzheimer's and the best pathological correlate of the characteristic cognitive decline.

“Importantly, we found that this potential interaction may occur at the synapses, believed to be the earliest affected structure in the context of Alzheimer’s and the best pathological correlate of the characteristic cognitive decline [17, 56, 67].”

• cites [17] DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ana.410270502 sourceNot checked — no full text of the source
• cites [56] Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012 sourceNot checked — no full text of the source
• cites [67] Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al (1991) Physical basis of cognitive alterations in alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The relationship between Aβ and synapses has been widely studied.

“The relationship between Aβ and synapses has been widely studied [19, 71].”

• cites [19] Forner S, Baglietto-Vargas D, Martini AC, Trujillo-Estrada L, LaFerla FM (2017) Synaptic impairment in Alzheimer’s disease: a dysregulated symphony. Trends Neurosci 40:347–357. https://doi.org/10.1016/j.tins.2017.04.002 sourceNot checked — no full text of the source
• cites [71] Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL (2023) Synaptic degeneration in Alzheimer disease. Nat Rev Neurol 19:19–38. https://doi.org/10.1038/s41582-022-00749-z sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The immunostaining, image acquisition, image processing and analyses were performed blinded to the clinicopathological diagnosis.

“The immunostaining, image acquisition, image processing and analyses were performed blinded to the clinicopathological diagnosis.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Experimenters administering jelly were blind to condition.

“Mice were weighed at the beginning of each week to determine the weight of jelly to be given for that week, and were dosed daily for one month with jelly containing vehicle or CT1812 10 mg/kg/day (experimenters administering jelly were blind to condition).”

Probably not a substantial claim.

Most binding partners have not been studied in human brain nor using human derived Aβ species.

“It is relevant to note that most binding partners have not been studied in human brain nor using human derived Aβ species [38, 63].”

• cites [38] Li S, Selkoe DJ (2020) A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain. J Neurochem 154:583–597. https://doi.org/10.1111/jnc.15007 sourceCheck pending
• cites [63] Smith LM, Strittmatter SM (2017) Binding sites for amyloid-β oligomers and synaptic toxicity. Cold Spring Harb Perspect Med 7:a024075. https://doi.org/10.1101/cshperspect.a024075 sourceCheck pending

It may state two separate claims as one.

In Alzheimer's brain, TMEM97 levels were increased in synapses, and TMEM97 was found in close enough proximity to Aβ to be binding.

“In Alzheimer’s brain, TMEM97 levels were increased in synapses, and TMEM97 was found in close enough proximity to Aβ to be binding.”

Probably not a substantial claim. It may state two separate claims as one.

Aβ fibrils bind non-specifically to a variety of surfaces, and Aβ monomers bind to several receptors when applied exogenously.

“Further, while Aβ fibrils bind non-specifically to a variety of surfaces, and Aβ monomers bind to several receptors when applied exogenously [5], Aβ oligomers have been shown to bind saturably to a single site[27, 62] suggesting specific pharmacological interactions with receptors.”

• cites [5] Benilova I, De Strooper B (2013) Promiscuous Alzheimer’s amyloid: yet another partner. Science 341:1354–1355. https://doi.org/10.1126/science.1244166 sourceNot checked — no full text of the source

It may state two separate claims as one.

This potential interaction may occur at the synapses, believed to be the earliest affected structure in the context of Alzheimer's and the best pathological correlate of the characteristic cognitive decline.

“Importantly, we found that this potential interaction may occur at the synapses, believed to be the earliest affected structure in the context of Alzheimer’s and the best pathological correlate of the characteristic cognitive decline [17, 56, 67].”

• cites [17] DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ana.410270502 sourceNot checked — no full text of the source
• cites [56] Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012 sourceNot checked — no full text of the source
• cites [67] Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al (1991) Physical basis of cognitive alterations in alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

Other binding partners that have been suggested to bind Aβ include the α7-nicotinic receptor, Ephrin A4 (EphA4), PSD95 or LilrB2.

“Other binding partners that have been suggested to bind Aβ include the α7-nicotinic receptor [49], Ephrin A4 (EphA4) [73], PSD95 [35, 50, 52] or LilrB2 [32].”

• cites [49] Parri HR, Hernandez CM, Dineley KT (2011) Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82:931–942. https://doi.org/10.1016/j.bcp.2011.06.039 sourceCheck pending
• cites [73] Vargas LM, Leal N, Estrada LD, González A, Serrano F, Araya K et al (2014) EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers. PLoS ONE 9:e92309. https://doi.org/10.1371/journal.pone.0092309 sourceCheck pending
• cites [35] Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL et al (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200. https://doi.org/10.1523/JNEUROSCI.3432-04.2004 sourceNot checked yet

It may state two separate claims as one.

In mouse and human iPSC models, Aβ is in close proximity to TMEM97 in synapses and CT1812 treatment to disrupt this interaction is beneficial.

“Further we confirm in mouse and human iPSC models that Aβ is in close proximity to TMEM97 in synapses and that CT1812 treatment to disrupt this interaction is beneficial.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Each experiment was repeated with three different differentiations of each of the three lines.

“Each experiment was repeated with three different differentiations of each of the three lines.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Post-mortem interval (PMI) was slightly longer in the Alzheimer's group (Welch's t test, t = − 2.36, p = 0.030).

“Post-mortem interval (PMI) was slightly longer in Alzheimer’s group (Welch’s t test, t = − 2.36, p = 0.030).”

Probably not a substantial claim.

Only those objects detected in more than one consecutive section (3D objects) were quantified, allowing us to reduce non-specific signals.

“Importantly, only those objects detected in more than one consecutive Sect. (3D objects) were quantified, allowing us to reduce non-specific signals.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Bias was minimized by setting the same parameters for image acquisition and image analysis for all the included cases.

“Bias was also minimized by setting the same parameters for image acquisition and image analysis for all the included cases.”

Probably not a substantial claim. It may state two separate claims as one.

In AD cases, images were acquired with a plaque in the field since our previous work demonstrated that synaptic Aβ accumulation is most prominent around plaques.

“In AD cases, images were acquired with a plaque in the field since our previous work demonstrated that synaptic Aβ accumulation is most prominent around plaques [29, 34].”

• cites [29] Jackson RJ, Rose J, Tulloch J, Henstridge C, Smith C, Spires-Jones TL (2019) Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers. Brain Commun 1:fcz003. https://doi.org/10.1093/braincomms/fcz003 sourceCheck pending
• cites [34] Koffie RM, Hashimoto T, Tai H-C, Kay KR, Serrano-Pozo A, Joyner D et al (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135:2155–2168. https://doi.org/10.1093/brain/aws127 sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

A post-hoc power calculation using the results from the primary question in this study-whether Aβ and TMEM97 generate a FRET signal in human synapses-indicates that with our n and effect size, we have 100% power to detect a positive FRET signal.

“A post-hoc power calculation using the results from the primary question in this study—whether Aβ and TMEM97 generate a FRET signal in human synapses—indicates that with our n and effect size, we have 100% power to detect a positive FRET signal (effect size 3.8 based on the % Aβ-TMEM97 FRET positive pixels within PSDs 38.4% ± 9.66 and the biological negative control—the % PSD-synaptophysin FRET”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

The precise binding location of CT1812 has not been directly determined.

“the precise binding location of CT1812 has not been directly determined”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

A previously published model proposes that CT1812 does not compete directly with oligomers at the same site.

“Therefore suggesting that CT1812 does not compete directly with oligomers at the same site [28]”

• cites [28] Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R et al (2021) Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer’s disease modification. Alzheimers Dement 17:1365–1382. https://doi.org/10.1002/alz.12302 sourceNot checked yet

Probably not a substantial claim.

We cannot rule out that Aβ may be binding to other nearby proteins instead of directly interacting with TMEM97.

“we cannot rule out that Aβ may be binding to other nearby proteins instead of directly interacting with TMEM97”

Probably not a substantial claim. The paper may give no reason why it holds.

This interaction can be modulated by drugs.

“which is important as this interaction can be modulated by drugs”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

TMEM97 is thought to be an endo-lysosome-related protein linked to cellular toxicity and essential for the internalization of cholesterol molecules like LDL through the formation of a complex with PGRMC1.

“TMEM97 is thought to be an endo-lysosome-related protein which has itself been linked to cellular toxicity and is essential for the internalization of cholesterol molecules like LDL through the formation of a complex with PGRMC1 [4, 55]”

• cites [4] Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T et al (2009) Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Metab 10:63–75. https://doi.org/10.1016/j.cmet.2009.05.009 sourceNot checked — no full text of the source
• cites [55] Riad A, Zeng C, Weng C-C, Winters H, Xu K, Makvandi M 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 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

CHI3L1 encodes YKL-40 protein, is expressed in astrocytes, and is a biomarker of inflammation in Alzheimer's disease.

“CHI3L1, which encodes YKL-40 protein, is expressed in astrocytes and is a biomarker of inflammation in Alzheimer’s disease [48]”

• cites [48] Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M et al (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15:673–684. https://doi.org/10.1016/S1474-4422(16)00070-3 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

In tumor cells, the canonical Sigma-2 ligand DTG binds to Sigma-2 receptors at a location on the TMEM97 protein.

“In tumor cells, the canonical Sigma-2 ligand DTG binds to Sigma-2 receptors at a location on the TMEM97 protein [3]”

• cites [3] Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC (2017) Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci USA 114:7160–7165. https://doi.org/10.1073/pnas.1705154114 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it.

We only had capacity to image 1-2 cell lines per group in the 24 h condition.

“we only had capacity to image 1–2 cell lines per group (albeit with hundreds of imaged objects) in the 24 h condition”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

PCDHGB4 is a cell adhesion molecule on neuronal synapses involved in synaptic maturation and stabilization.

“a cell adhesion molecule on neuronal synapses, which is involved in synaptic maturation and stabilization [36]”

• cites [36] LaMassa N, Sverdlov H, Mambetalieva A, Shapiro S, Bucaro M, Fernandez-Monreal M et al (2021) Gamma-protocadherin localization at the synapse is associated with parameters of synaptic maturation. J Comp Neurol 529:2407–2417. https://doi.org/10.1002/cne.25102 sourceCheck pending