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Cited by 55Pharmacological Receptor Mechanisms and EffectsAlzheimer's disease research and treatmentsParkinson's Disease Mechanisms and Treatments

The DOI matches its Crossref record; 182 of the 187 references it cites were found in a registry or an index; 9 of the 178 sources its claims cite were checked for support.

Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases

Open access
Lizama, Britney N., Kahle, Jennifer, Catalano, Susan M., Caggiano, Anthony O., Grundman, Michael, Hamby, Mary E.·2023·International Journal of Molecular Sciences
DOI 10.3390/ijms24076251PMC PMC10093856
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Abstract

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes evidence that the sigma-2 receptor (S2R/TMEM97) regulates autophagy, cholesterol trafficking, and synaptic toxicity of amyloid-β and α-synuclein oligomers, positioning it as a therapeutic target for age-related CNS degenerative diseases. It highlights preclinical and early clinical development of S2R modulators such as CT1812 for Alzheimer’s disease, dementia with Lewy bodies, and dry AMD.

Key findings

  • S2R is encoded by TMEM97 and acts with PGRMC1, LDLR, and NPC1; it regulates autophagy, cholesterol homeostasis, membrane trafficking, and clearance/toxicity of amyloid-β and α-synuclein oligomers.
  • In Alzheimer’s disease brain tissue, TMEM97 expression is increased ~1.5-fold and localized to a ~1.8-fold greater proportion of synapses versus controls; CT1812 dose-dependently reduces S2R–amyloid-β interaction and phenocopies the protective A673T mutation with a four-fold reduction in amyloid-β oligomer binding.
  • In preclinical models, S2R modulators (e.g., CT1812, CT0093, CT0109, CT1344, CT1346) protect synapses and rescue memory/cognitive deficits in Alzheimer’s mouse models; α-synuclein oligomer-induced membrane trafficking inhibition is four-fold higher than with high monomer concentrations, and S2R modulators reverse it.
  • For dry AMD, a TMEM-VTN locus SNP is associated with decreased risk; the GATHER2 Phase 3 trial of Zimura showed a 14.3% reduction (p = 0.0064) in geographic atrophy growth, and pegcetacoplan was FDA-approved in February 2023, though S2R-targeted trials are planned or ongoing.

Methods

  • Narrative review; no primary data collection. It synthesizes published basic, preclinical, and clinical literature on S2R/TMEM97 biology and therapeutic development.
  • Covers age-related degenerative CNS diseases: Alzheimer’s disease, α-synucleinopathies (Parkinson’s disease, dementia with Lewy bodies), dry AMD, and briefly Niemann–Pick type C, schizophrenia, and Huntington’s disease.
  • Main analysis is qualitative evidence synthesis, including cited genetic, pharmacological, cell-based, animal-model, and clinical trial findings.

Limitations

  • Stated: endogenous ligand(s) remain uncertain; histatin-1 is enriched in salivary glands/tears, and 20(S)-OHC is a candidate requiring further validation.
  • Stated: precise molecular mechanisms, cell-type-specific interactions, and protein arrangements (phosphorylation, dimerization, heme binding) of S2R/TMEM97 are not fully discovered; dry AMD models cannot faithfully recapitulate human pathology, and TMEM97 knockout results conflict by stressor.
  • Stated: whether preclinical efficacy translates to the clinic is unknown; evident: as a narrative review, no systematic search, inclusion criteria, or risk-of-bias assessment is described.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms24076251

Cites

182 of 182 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

9 of 178 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ARIA-E occurred in 35.2% of individuals treated with aducanumab in Phase 3 clinical trials.

    “Similarly, ARIA-E occurred in 35.2% of individuals treated with aducanumab in Phase 3 clinical trials [26].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Salloway, 2022, Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease, JAMA Neurol. source

      The Results report ARIA-E in 362 of 1029 participants (35.2%) receiving 10 mg/kg aducanumab in the two phase 3 trials. The claim omits that dose qualifier: the Results give different rates for the 3-mg/kg and 6-mg/kg groups, so 35.2% does not describe all aducanumab-treated participants. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Reduction or ablation of S2R activity was observed when TMEM97 expression was reduced or absent in calf liver cells or human cervical cancer cells.

    “This was confirmed in pharmacological studies assessing the activity of S2R ligands where reduction, or ablation, of S2R activity was observed when TMEM97 expression was reduced, or absent, in calf liver cells [16,61] or human cervical cancer cells [66], respectively.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [16] Schmidt, 2019, The Molecular Function of σ Receptors: Past, Present, and Future, Trends Pharmacol. Sci. source
    • cites [61] Alon, 2017, Identification of the Gene That Codes for the σ 2 Receptor, Proc. Natl. Acad. Sci. USA source
    • cites [66] Riad, 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. source

      The Results sections on CRISPR gene editing and in vitro binding studies report that TMEM97 was knocked out in HeLa cells and that binding of the sigma-2 receptor ligand [125I]RHM-4 was completely lost. The paper measures ligand binding, not a general ablation of S2R activity; it also reports residual binding of a second ligand, [3H]DTG. The calf-liver portion is attributed to other citations, not this paper. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Amyloid-β oligomers are suggested to be the most neurotoxic forms of amyloid protein implicated in the neurodegeneration observed in Alzheimer's disease.

    “which are suggested to be the most neurotoxic forms of amyloid protein implicated in the neurodegeneration observed in Alzheimer’s disease [32].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [32] Larson, 2012, Soluble Aβ Oligomer Production and Toxicity, J. Neurochem. source
  • Premisecitation

    S2R modulators have been shown to ameliorate amyloid-β oligomer and α-synuclein oligomer-mediated deficits in neuronal trafficking.

    “Indeed, S2R modulators have been shown to ameliorate amyloid-β oligomer and α-synuclein oligomer-mediated deficits in neuronal trafficking [2,3,4]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [2] Izzo, N.J., Staniszewski, A., To, L., Fa, M., Teich, A.F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., and Wardius, M. (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. source

      The Results (Figure 9; page unavailable) show that sigma-2/PGRMC1 antagonists prevent or reverse amyloid-β oligomer-induced membrane-trafficking deficits in neuronal cultures. Our copy does not show that they ameliorate α-synuclein oligomer-induced trafficking deficits; the α-synuclein mention found is in the References. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [3] Izzo, N.J., Xu, J., Zeng, C., Kirk, M.J., Mozzoni, K., Silky, C., Rehak, C., Yurko, R., Look, G., and Rishton, G. (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. source

      The Results section says sigma-2-selective small molecules prevent and reverse amyloid-β oligomer-induced membrane-trafficking deficits in neuronal cultures. The cited paper does not address α-synuclein oligomer-mediated trafficking deficits, so it supports only the amyloid-β part of the sentence. Page numbers are not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source
  • Premisecitation

    Several S2R modulators (CT0093, CT0109, CT1344, CT1346, and CT1812) rescued memory and cognitive deficits in an Alzheimer's mouse model.

    “Independently, several S2R modulators (CT0093, CT0109, CT1344, CT1346, and CT1812) rescued memory and cognitive deficits in an Alzheimer’s mouse model [2,64] (Figure 5).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [2] Izzo, N.J., Staniszewski, A., To, L., Fa, M., Teich, A.F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., and Wardius, M. (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. source

      The Results section (‘Anti-Abeta compounds are effective in vivo,’ Fig. 13) reports improved memory in transgenic Alzheimer’s-model mice treated with CT01344 or CT01346, apparently the compounds cited as CT1344 and CT1346. It reports that CT0093 and CT0109 prevented oligomer-induced memory deficits in wild-type mice, not that they rescued deficits in the transgenic model. The passages found do not report a mouse-memory result for CT1812. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Izzo, 2021, Preclinical and Clinical Biomarker Studies of CT1812: A Novel Approach to Alzheimer’s Disease Modification, Alzheimer’s Dement. source
  • It may state two separate claims as one. 55
  • Probably not a substantial claim. 6

  • It may state two separate claims as one.

    Premisecitation

    Within the brain, S2R is found in the cerebellum, cortex, hippocampus, and substantia nigra, and is enriched in neurons compared with glial cells in the adult brain.

    “Within the brain, S2R is found in several areas, including the cerebellum, cortex, hippocampus, and substantia nigra, and is enriched in neurons as compared with glial cells in the adult brain [1].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Karlsson, 2021, A Single–Cell Type Transcriptomics Map of Human Tissues, Sci. Adv. source

      The Results section discusses cell-type expression across tissues but does not report S2R expression in the named brain regions or compare its expression in adult neurons and glial cells. Searches for S2R, TMEM97, sigma-2 receptor, and the neuron–glia comparison found no passage addressing the claim; the brain-atlas entries in the References do not establish it. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Specific small-molecule ligands that bind to S2R displace endogenous β-amyloid oligomers from human brain samples from individuals with Alzheimer's disease, displace β-amyloid oligomer binding to primary cultured neurons, and reverse cognitive deficits in Alzheimer model mice.

    “This is consistent with results showing that specific small-molecule ligands that bind to S2R displace endogenous β-amyloid oligomers from human brain samples from individuals with Alzheimer’s disease, displace β-amyloid oligomer binding to primary cultured neurons, and reverse cognitive deficits in Alzheimer model mice [2,3].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [2] Izzo, N.J., Staniszewski, A., To, L., Fa, M., Teich, A.F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., and Wardius, M. (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. source

      Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [3] Izzo, N.J., Xu, J., Zeng, C., Kirk, M.J., Mozzoni, K., Silky, C., Rehak, C., Yurko, R., Look, G., and Rishton, G. (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. source

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

    Interpretationreasoning

    Targeting S2R represents a novel approach that is functionally distinct from other current approaches in the development of clinical treatments of degenerative diseases.

    “Targeting S2R represents a novel approach that is functionally distinct from other current approaches in the development of clinical treatments of degenerative diseases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    S2R regulates cell functions disrupted in disease, including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface.

    “S2R is a four-domain transmembrane receptor, also known as transmembrane protein 97 (TMEM97), that is expressed in multiple cell types susceptible to degeneration, including neurons [1], and regulates cell functions disrupted in disease, including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and receptor stabilization at the cell”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Karlsson, 2021, A Single–Cell Type Transcriptomics Map of Human Tissues, Sci. Adv. source

  • It may state two separate claims as one.

    Premisecitation

    The sigma-2 receptor (S2R) is encoded by TMEM97, and S2R and TMEM97 are one and the same.

    “In 2017, the S2R was cloned [61], demonstrating that TMEM97, not PGRMC1, was the gene encoding S2R, indicating that S2R and TMEM97 are one and the same.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Alon, 2017, Identification of the Gene That Codes for the σ 2 Receptor, Proc. Natl. Acad. Sci. USA source

  • It may state two separate claims as one.

    Premisecitation

    S2R is a four-domain transmembrane receptor, also known as transmembrane protein 97 (TMEM97), expressed in multiple cell types susceptible to degeneration, including neurons.

    “S2R is a four-domain transmembrane receptor, also known as transmembrane protein 97 (TMEM97), that is expressed in multiple cell types susceptible to degeneration, including neurons [1]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Karlsson, 2021, A Single–Cell Type Transcriptomics Map of Human Tissues, Sci. Adv. source

  • It may state two separate claims as one.

    Premisenone given

    The medications noted above do not alter the progression of the underlying Alzheimer's disease and provide only modest efficacy in treating symptoms.

    “The medications noted above do not alter the progression of the underlying disease and provide only modest efficacy in treating symptoms.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Two anti-amyloid-β monoclonal antibodies have been approved by the FDA for the treatment of early-stage Alzheimer's disease: aducanumab and lecanemab.

    “Two anti-amyloid-β monoclonal antibodies have been approved by the Food and Drug Administration (FDA) for the treatment of early-stage Alzheimer’s disease.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Modulation of S2R may ameliorate dysfunctional cellular processes and slow degenerative progression.

    “Modulation of S2R may ameliorate dysfunctional cellular processes and slow degenerative progression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisereasoning

    The approval of pegcetacoplan was based on positive 24-month results from the Derby and Oaks studies, which both showed decreases in the change in geographic atrophy lesion size from baseline with pegcetacoplan treatment.

    “The approval was based on positive 24-month results from Apellis’ late-stage Derby and Oaks studies, which both showed robust and consistent decreases in the change in geographic atrophy lesion size from baseline with pegcetacoplan treatment.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Treatment with S2R ligands induces processing of LC3, formation of autophagic vacuoles, and expression of downstream effectors of the mammalian Target of Rapamycin (mTOR) pathway.

    “Treatment with S2R ligands induces processing of LC3, formation of autophagic vacuoles, and expression of downstream effectors of the mammalian Target of Rapamycin (mTOR) pathway [118].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Zeng, 2012, Sigma-2 Ligands Induce Tumour Cell Death by Multiple Signalling Pathways, Br. J. Cancer source

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

    Premisenone given

    α-Synucleinopathies share a characteristic accumulation of α-synuclein aggregates into fibrils, the major constituent of Lewy bodies that occur inside brain neurons in both Parkinson's disease and dementia with Lewy bodies.

    “α-synucleinopathies share a characteristic accumulation of α-synuclein aggregates into fibrils, the major constituent of the Lewy bodies that occur inside brain neurons in both diseases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Some small molecule modulators of S2R, such as siramesine and SV119, trigger the induction of autophagy, while other S2R modulators such as CT2168 can restore α-synuclein oligomer-induced deficits in lysosomal-associated membrane protein 2A levels back to healthy control levels in neurons.

    “Some small molecule modulators of S2R, such as siramesine and SV119, trigger the induction of autophagy [118,120], while other S2R modulators such as CT2168 can restore α-synuclein oligomer-induced deficits in lysosomal-associated membrane protein 2A levels, an indirect marker of autophagy, back to healthy control levels in neurons [4].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Zeng, 2012, Sigma-2 Ligands Induce Tumour Cell Death by Multiple Signalling Pathways, Br. J. Cancer source
    • cites [120] Ostenfeld, 2008, Anti-Cancer Agent Siramesine Is a Lysosomotropic Detergent That Induces Cytoprotective Autophagosome Accumulation, Autophagy source
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source

  • It may state two separate claims as one.

    Premisecitation

    TMEM97 knockout cell lines exhibit aberrant autophagic flux and lysosome dysfunction.

    “TMEM97 knockout cell lines exhibit aberrant autophagic flux and lysosome dysfunction [119].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Shen, 2021, TMEM97 Ablation Aggravates Oxidant-Induced Retinal Degeneration, Cell Signal. source

  • It may state two separate claims as one.

    Premisecitation

    Increased expression of TMEM97 correlated with a rise in expression of genes involved in lipid metabolism, and these genes were significantly associated with the gene ontology terms cellular lipid, isoprenoid, cholesterol, and long-chain fatty-acyl-CoA biosynthetic processes.

    “Interestingly, increased expression of TMEM97 correlated with a rise in expression of genes involved in lipid metabolism, and these genes were significantly associated with the gene ontology terms cellular lipid, isoprenoid, cholesterol, and long-chain fatty-acyl-CoA biosynthetic processes [79]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Lafyatis, 2017, Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82, J. Investig. Dermatol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisenone given

    α-Synucleinopathies are a group of neurodegenerative disorders in which the protein α-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.

    “α-Synucleinopathies are a group of neurodegenerative disorders in which the protein α-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisereasoning

    Thickening of Bruch's membrane disrupts the cytoarchitecture of the retinal pigment epithelium, and this disruption coupled with oxidative stress and inflammation leads to diminished health and function of retinal pigment epithelial and photoreceptor cells, with accumulated damage resulting in cell death and visual impairment.

    “This thickening disrupts the cytoarchitecture of the retinal pigment epithelium, and this disruption, coupled with oxidative stress and inflammation, leads to the diminished health and function of retinal pigment epithelial and photoreceptor cells, with accumulated damage resulting in cell death and visual impairment.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Increasing evidence suggests that α-synuclein also forms soluble oligomers, and that oligomers are more toxic than fibrils.

    “Increasing evidence suggests that α-synuclein also forms soluble oligomers, and that oligomers are more toxic than fibrils [33,34,35].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Karpinar, 2009, Pre-Fibrillar α-Synuclein Variants with Impaired β-Structure Increase Neurotoxicity in Parkinson’s Disease Models, EMBO J. source
    • cites [34] Outeiro, T.F., Putcha, P., Tetzlaff, J.E., Spoelgen, R., Koker, M., Carvalho, F., Hyman, B.T., and McLean, P.J. (2008). Formation of Toxic Oligomeric Alpha-Synuclein Species in Living Cells. PLoS ONE, 3. source
    • cites [35] Cremades, 2012, Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein, Cell source

  • It may state two separate claims as one.

    Premisecitation

    The crystal structure of TMEM97, although bovine, was resolved in 2021 and illuminated the docking sites of small molecule S2R ligands PB28 and roluperidone.

    “The crystal structure of TMEM97, although bovine, was resolved in 2021 which illuminated the docking sites of small molecule S2R ligands, PB28, and roluperidone [63]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Alon, 2021, Structures of the Σ2 Receptor Enable Docking for Bioactive Ligand Discovery, Nature source

  • It may state two separate claims as one.

    Premisecitation

    Dry age-related macular degeneration involves a dysregulation of cellular processes, among which is the accumulation of lipid deposits known as drusen that causes a thickening of Bruch's membrane.

    “Dry AMD involves a dysregulation of cellular processes, among which is the accumulation of lipid deposits, known as drusen, that causes a thickening of Bruch’s membrane [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Mitchell, 2018, Age-Related Macular Degeneration, Lancet source

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

    Interpretationcitation

    Given that most treatments in development for dry age-related macular degeneration are invasive, an orally delivered small-molecule approach targeting S2R would offer several advantages over these approaches and/or may be a complementary approach in combination with invasive therapeutics if proven efficacious in clinical trials.

    “Given that most of the treatments in development are invasive in nature [45], an orally delivered small-molecule approach targeting S2R would offer several advantages over these approaches and/or may be a complementary approach in combination with invasive therapeutics if proven efficacious in clinical trials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Mitchell, 2018, Age-Related Macular Degeneration, Lancet source

  • It may state two separate claims as one.

    Premisereasoning

    S2R is a therapeutic target under investigation for α-synucleinopathies, and CT1812 is currently in Phase 2 trials for dementia with Lewy bodies.

    “The S2R is a therapeutic target under investigation for α-synucleinopathies and CT1812 is currently in Phase 2 trials, being developed by Cognition Therapeutics, for dementia with Lewy bodies (NCT05225415).”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    There are currently no disease-modifying treatments approved for individuals with dementia with Lewy bodies.

    “There are currently no disease-modifying treatments approved for individuals with dementia with Lewy bodies.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    TMEM97 is a member of the EXPERA family of proteins along with emopamil binding protein (EBP), a protein domain containing four transmembrane regions and thought to have sterol isomerase activity.

    “TMEM97 is a member of the EXPERA (EXPanded EBP superfamily) family of proteins along with emopamil binding protein (EBP), which is a protein domain containing four transmembrane regions and thought to have sterol isomerase activity [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Ponting, 2014, TM6SF2 and MAC30, New Enzyme Homologs in Sterol Metabolism and Common Metabolic Disease, Front. Genet.

  • It may state two separate claims as one.

    Premisecitation

    TMEM97 levels can be regulated by changes in cholesterol levels; when cholesterol levels are reduced, TMEM97 expression can be induced by sterol regulatory element-binding protein-2.

    “Although TMEM97, unlike emopamil binding protein, is not thought to have isomerase activity, TMEM97 levels can be regulated by changes in cholesterol levels. More specifically, when cholesterol levels are reduced, TMEM97 expression can be induced by sterol regulatory element-binding protein-2 [75,76,77,78].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [75] Ahmed, 2012, S2R(Pgrmc1): The Cytochrome-Related Sigma-2 Receptor That Regulates Lipid and Drug Metabolism and Hormone Signaling, Expert Opin. Drug Metab. Toxicol. source
    • cites [76] Lee, 2018, Loss of Progesterone Receptor Membrane Component 1 Promotes Hepatic Steatosis via the Induced de Novo Lipogenesis, Sci. Rep. source
    • cites [77] Cai, 2015, A Potential Mechanism Underlying Atypical Antipsychotics-Induced Lipid Disturbances, Transl. Psychiatry source
    • cites [78] Hughes, 2007, Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes, Cell Metab. source

  • It may state two separate claims as one.

    Premisecitation

    Both TMEM97 and PGRMC1 were regulated at the transcript level in skin cells by the topically applied Wnt/beta-catenin inhibitor C-82, suggesting that Wnt signaling regulates TMEM97.

    “Both TMEM97 and PGRMC1 were regulated at the transcript level in skin cells by the topically applied Wnt/beta-catenin inhibitor C-82 under investigation in a clinical trial in individuals with systemic sclerosis, suggesting that Wnt signaling regulates TMEM97 [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Lafyatis, 2017, Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82, J. Investig. Dermatol. source

  • It may state two separate claims as one.

    Premisecitation

    Support for targeting S2R derives from α-synuclein binding to PrPc and the finding that S2R modulators block α-synuclein oligomer toxicity in neurons.

    “Support for targeting the S2R derives from α-synuclein binding to PrPc [42], and the finding that S2R modulators block α-synuclein oligomer toxicity in neurons [4]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Thom, 2022, Cellular Prion Protein Mediates α-Synuclein Uptake, Localization, and Toxicity In Vitro and In Vivo, Mov. Disord. source
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source

  • It may state two separate claims as one.

    Premisecitation

    Later studies by two independent groups found that S2R binding activity was not altered irrespective of the level of PGRMC1 expressed, and full activity persisted even in the absence of PGRMC1.

    “In later studies by two independent groups, however, in which PGRMC1 levels were genetically manipulated through overexpression or depletion, S2R binding activity was not altered irrespective of the level of PGRMC1 expressed, as assessed using the canonical S2R ligand tritiated di-o-tolylguanidine binding in the presence of saturating (+)-pentazocine, in a human epithelial cell line or a mouse mot”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Abate, 2015, Elements in Support of the ‘ Non-Identity ’ of the PGRMC1 Protein with the σ 2 Receptor, Eur. J. Pharmacol. source
    • cites [56] Chu, 2015, The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 Are Different Binding Sites Derived From Independent Genes, EBioMedicine source

  • It may state two separate claims as one.

    Premisecitation

    S2R activity was initially localized to a ~20 kDa membrane protein and first thought to be progesterone receptor membrane component 1 (PGRMC1).

    “S2R activity was initially localized to a ~20 kDa membrane protein [51,52] and first thought to be progesterone receptor membrane component 1 (PGRMC1), based on mass spectrophotometry identification following an immunoaffinity pull down with an irreversible S2R ligand binder WC-11, physiochemical properties, and pharmacological evidence [53,54].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [51] Hellewell, 1990, A Sigma-like Binding Site in Rat Pheochromocytoma (PC12) Cells: Decreased Affinity for (+)-Benzomorphans and Lower Molecular Weight Suggest a Different Sigma Receptor Form from That of Guinea Pig Brain, Brain Res. source
    • cites [52] Hellewell, 1994, Rat Liver and Kidney Contain High Densities of Sigma 1 and Sigma 2 Receptors: Characterization by Ligand Binding and Photoaffinity Labeling, Eur. J. Pharmacol. source
    • cites [53] Zeng, 2016, The PGRMC1 Protein Level Correlates with the Binding Activity of a Sigma-2 Fluorescent Probe (SW120) in Rat Brain Cells, Mol. Imaging Biol. source
    • cites [54] Nicholson, 2016, Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastomas, J. Pharmacol. Exp. Ther. source

  • It may state two separate claims as one.

    Premisecitation

    Blocking the interaction between apolipoprotein E and PGRMC1 increases amyloid-β clearance from the brain, reduces amyloid-β deposition, and reduces related pathology in Alzheimer animal models.

    “Blocking the interaction between apolipoprotein E and PGRMC1 increases amyloid-β clearance from the brain, reduces amyloid-β deposition, and reduces related pathology in Alzheimer animal models [124].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Wisniewski, 2020, APOE-Amyloid Interaction: Therapeutic Targets, Neurobiol. Dis. source

  • It may state two separate claims as one.

    Premisecitation

    Amyloid-β oligomer binding to neuronal synapses is abrogated by knockdown of PGRMC1, PrPc, and with S2R modulators in neurons.

    “Amyloid-β oligomer binding to neuronal synapses is abrogated by knockdown of PGRMC1 [3], PrPc, and with S2R modulators in neurons [2,3]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Izzo, N.J., Xu, J., Zeng, C., Kirk, M.J., Mozzoni, K., Silky, C., Rehak, C., Yurko, R., Look, G., and Rishton, G. (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. source
    • cites [2] Izzo, N.J., Staniszewski, A., To, L., Fa, M., Teich, A.F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., and Wardius, M. (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. source

  • It may state two separate claims as one.

    Premisecitation

    Synaptic loss is a hallmark of Alzheimer's disease and other neurodegenerative diseases in which there is a significant, progressive reduction of synaptic density in disease-related brain regions.

    “Synaptic loss is a hallmark of Alzheimer’s disease [132] and other neurodegenerative diseases in which there is a significant, progressive reduction of synaptic density in disease-related brain regions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Tzioras, 2023, Synaptic Degeneration in Alzheimer Disease, Nat. Rev. Neurol. source

  • It may state two separate claims as one.

    Premisecitation

    In vivo, the S2R modulator SAS-0132 produces neuroprotective, cognitive enhancing, and anti-inflammatory effects in a rodent model of Alzheimer's disease.

    “In vivo, the S2R modulator SAS-0132 has been shown to produce neuroprotective, cognitive enhancing, and anti-inflammatory effects in a rodent model of Alzheimer’s disease [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Yi, 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. source

  • It may state two separate claims as one.

    Premisecitation

    Amyloid-β oligomer binding results in aberrant neuronal signaling and the endocytosis of the dysfunctional synapse into the cell.

    “Amyloid-β oligomer binding results in aberrant neuronal signaling and the endocytosis of the dysfunctional synapse into the cell [126,127].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [126] Um, 2013, Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein, Neuron source
    • cites [127] Spurrier, 2022, Reversal of Synapse Loss in Alzheimer Mouse Models by Targeting MGluR5 to Prevent Synaptic Tagging by C1Q, Sci. Transl. Med. source

  • It may state two separate claims as one.

    Premisecitation

    S2R modulators tested by several independent groups are neuroprotective, synaptoprotective, block toxic amyloid-β oligomers from binding to neuronal synapses, and restore neuronal functioning and cognitive deficits across various preclinical models.

    “S2R modulators tested by several independent groups have been shown to be neuroprotective, be synaptoprotective, block toxic amyloid-β oligomers from binding to neuronal synapses, and restore neuronal functioning and cognitive deficits across various preclinical models, from neurons in culture to in vivo Alzheimer’s disease models from C. elegans to rodents [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Yi, 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. source

  • It may state two separate claims as one.

    Premisecitation

    Synaptic loss is not necessarily permanent and synapses can be regained or formed again once amyloid-β oligomers are removed.

    “Synaptic loss, however, is not necessarily permanent and synapses can be regained or formed again once amyloid-β oligomers are removed [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Izzo, 2021, Preclinical and Clinical Biomarker Studies of CT1812: A Novel Approach to Alzheimer’s Disease Modification, Alzheimer’s Dement. source

  • It may state two separate claims as one.

    Premisecitation

    Axonal guidance cues are reactivated in adults and are important in establishing long-term potentiation in the adult organism.

    “While axonal guidance mechanisms are active in developing organisms and stabilize by adulthood, axonal guidance cues are “reactivated” in adults and are important in establishing long-term potentiation in the adult organism [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Glasgow, 2020, Guiding Synaptic Plasticity: Novel Roles for Netrin-1 in Synaptic Plasticity and Memory Formation in the Adult Brain, J. Physiol. source

  • It may state two separate claims as one.

    Premisecitation

    Accumulation of autophagic vacuoles has been observed in dystrophic neurites of Alzheimer brains using electron microscopy of post-mortem biopsies, suggesting that the autophagic pathway is impaired in affected neurons.

    “The accumulation of autophagic vacuoles has been observed in dystrophic neurites of Alzheimer brains using electron microscopy of post-mortem biopsies [149], suggesting that the autophagic pathway is indeed impaired in affected neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Nixon, 2005, Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study, J. Neuropathol. Exp. Neurol. source

  • It may state two separate claims as one.

    Premisecitation

    PGRMC1 is a heme binding protein and regulates carbon monoxide through oxidative heme degradation.

    “PGRMC1 is a heme binding protein [103,138] and regulates carbon monoxide through oxidative heme degradation [139].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Rohe, 2009, PGRMC1 (Progesterone Receptor Membrane Component 1): A Targetable Protein with Multiple Functions in Steroid Signaling, P450 Activation and Drug Binding, Pharmacol. Ther. source
    • cites [138] Kabe, 2016, Haem-Dependent Dimerization of PGRMC1/Sigma-2 Receptor Facilitates Cancer Proliferation and Chemoresistance, Nat. Commun. source
    • cites [139] Kabe, 2016, Cystathionine Beta-Synthase and PGRMC1 as CO Sensors, Free Radic. Biol. Med. source

  • It may state two separate claims as one.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Riad, 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. source

  • It may state two separate claims as one.

    Premisecitation

    Amyloid-β oligomers bind to synapses and interfere with normal neurotransmission, long-term potentiation, and memory formation.

    “As previously discussed, amyloid-β oligomers bind to synapses [144] and interfere with the normal process of neurotransmission, long-term potentiation, and thereby memory formation [145].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [144] Lacor, 2004, Synaptic Targeting by Alzheimer’s-Related Amyloid β Oligomers, J. Neurosci. source
    • cites [145] Selkoe, 2016, The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years, EMBO Mol. Med. source

  • It may state two separate claims as one.

    Premisecitation

    Pathological proteins associated with familial Alzheimer's disease are either autophagy substrates, such as amyloid-β and tau, or linked to autophagy regulation, such as presenilin and clusterin.

    “Moreover, pathological proteins associated with familial Alzheimer’s disease are either autophagy substrates, such as amyloid-β and tau, or linked to autophagy regulation, such as presenilin and clusterin [148].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Yoon, 2016, Alzheimer’s Disease Genes and Autophagy, Brain Res. source

  • It may state two separate claims as one.

    Premisecitation

    TMEM97 expression is significantly increased by approximately 1.5-fold in Alzheimer's disease and is localized to an increased proportion of approximately 1.8-fold of synapses in brain tissue from individuals with Alzheimer's disease compared with healthy controls.

    “Moreover, TMEM97 expression is significantly increased by ~1.5-fold in Alzheimer’s disease and is localized to an increased proportion (~1.8-fold) of synapses in brain tissue from individuals with Alzheimer’s disease when compared with healthy controls [65]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Colom-Cadena, M., Tulloch, J., Jackson, R.J., Catterson, J.H., Rose, J., Davies, C., Hooley, M., Anton-Fernandez, A., Dunnett, S., and Tempelaar, R. (2021). TMEM97 Increases in Synapses and Is a Potential Synaptic Aβ Binding Partner in Human Alzheimer’s Disease. bioRxiv. source

  • It may state two separate claims as one.

    Premisecitation

    S2R regulates cholesterol homeostasis by interacting with low-density lipoprotein receptor (LDLR) at the plasma membrane to transport apolipoprotein E into neurons and with NPC1 intracellularly to regulate LDL cholesterol transport out of lysosomes.

    “One important function of S2R is regulation of cholesterol homeostasis by interacting with low-density lipoprotein receptor (LDLR), an apolipoprotein-E receptor, at the plasma membrane to transport apolipoprotein E into neurons [66] and with NPC1, intracellularly, to regulate LDL cholesterol transport out of lysosomes [93,94].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Riad, 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. source
    • cites [93] Bartz, 2009, Identification of Cholesterol-Regulating Genes by Targeted RNAi Screening, Cell Metab. source
    • cites [94] Wahlster, 2015, Reduction of TMEM97 Increases NPC1 Protein Levels and Restores Cholesterol Trafficking in Niemann-Pick Type C1 Disease Cells, Hum. Mol. Genet.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Riad, 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. source

  • It may state two separate claims as one.

    Premisecitation

    S2R has been implicated in abnormal cholesterol trafficking in Niemann-Pick disease type C, and knockdown of S2R expression increased intracellular Niemann-Pick disease type C 1 protein and restored LDL-cholesterol and lysobisphosphatidic acid transport.

    “S2R has been implicated in the process of abnormal cholesterol trafficking in Niemann–Pick disease type C, and data have demonstrated that knockdown of S2R expression increased intracellular Niemann–Pick disease type C 1 protein and restored LDL-cholesterol and lysobisphosphatidic acid transport [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Wahlster, 2015, Reduction of TMEM97 Increases NPC1 Protein Levels and Restores Cholesterol Trafficking in Niemann-Pick Type C1 Disease Cells, Hum. Mol. Genet.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    S2R regulates synaptic plasticity and synaptic density in Alzheimer's disease, representing a fundamental mechanism underlying the loss of memory and further cognitive decline in Alzheimer's disease.

    “S2R regulates synaptic plasticity and synaptic density in Alzheimer’s disease, representing a fundamental mechanism underlying the devastating loss of memory and further cognitive decline in Alzheimer’s disease.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Similar to amyloid-β oligomers, α-synuclein oligomers interact with PrPc; α-synuclein interacts with PrPc to induce cognitive impairment through metabotropic glutamate receptors, and blockage of these glutamate receptor-mediated signaling events restores cognitive deficits.

    “Similar to amyloid-β oligomers, α-synuclein oligomers interact with PrPc [42]. α-Synuclein interacts with PrPc to induce cognitive impairment through metabotropic glutamate receptors, and blockage of these glutamate receptor-mediated signaling events restores cognitive deficits [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Thom, 2022, Cellular Prion Protein Mediates α-Synuclein Uptake, Localization, and Toxicity In Vitro and In Vivo, Mov. Disord. source

  • It may state two separate claims as one.

    Premisecitation

    α-Synuclein oligomers bind to neurons in culture and are internalized; with addition of an S2R modulator, the binding and thus internalization of the α-synuclein oligomers are inhibited.

    “α-Synuclein oligomers were found to bind to neurons in culture and are internalized (Figure 7 [4]). With the addition of an S2R modulator, the binding and thus internalization of the α-synuclein oligomers are inhibited (Figure 7 [4]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source

  • It may state two separate claims as one.

    Premisecitation

    α-Synuclein oligomers induce cellular stress responses, including aberrant autophagy-lysosome pathways, dysregulation of lipid metabolism, and a reduction in membrane trafficking.

    “α-Synuclein oligomers are known to induce cellular stress responses, including aberrant autophagy-lysosome pathways [161,162], dysregulation of lipid metabolism [163,164], and a reduction in membrane trafficking [4].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [161] Poehler, 2014, Autophagy Modulates SNCA/α-Synuclein Release, Thereby Generating a Hostile Microenvironment, Autophagy source
    • cites [162] Tang, 2021, Alpha-Synuclein Defects Autophagy by Impairing SNAP29-Mediated Autophagosome-Lysosome Fusion, Cell Death Dis. source
    • cites [163] Fanning, 2019, Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment, Mol. Cell source
    • cites [164] Colebc, 2002, Lipid Droplet Binding and Oligomerization Properties of the Parkinson’s Disease Protein α-Synuclein, J. Biol. Chem. source
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source

  • It may state two separate claims as one.

    Premisecitation

    Human genetics point to S2R as a promising therapeutic target for dry AMD, as several large-scale independent genome-wide association studies indicate that a single nucleotide polymorphism in the TMEM-VTN locus confers decreased risk for dry AMD.

    “First, human genetics point to S2R as a promising therapeutic target, as indicated via several large-scale, independent genome-wide association studies. These studies indicate that a single nucleotide polymorphism in the TMEM-VTN locus confers decreased risk for dry AMD [168,169].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [168] Fritsche, 2016, A Large Genome-Wide Association Study of Age-Related Macular Degeneration Highlights Contributions of Rare and Common Variants, Nat. Genet. source
    • cites [169] Yan, 2018, Genome-Wide Analysis of Disease Progression in Age-Related Macular Degeneration, Hum. Mol. Genet. source

  • It may state two separate claims as one.

    Premisecitation

    Neuronal pathology in α-synucleinopathies includes deficits in membrane trafficking and upregulation of lysosomal-associated membrane protein-2A, a protein critically required for chaperone-mediated autophagy.

    “More specifically, neuronal pathology observed in α-synucleinopathies includes deficits in membrane trafficking and an upregulation in lysosomal-associated membrane protein-2A, a protein critically required for chaperone-mediated autophagy [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Limegrover, 2021, Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-derived A-synuclein, J. Neurosci. Res. source

  • It may state two separate claims as one.

    Premisecitation

    CT1812 selectively prevents and displaces amyloid-β oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.

    “CT1812 selectively prevents and displaces amyloid-β oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Izzo, 2021, Preclinical and Clinical Biomarker Studies of CT1812: A Novel Approach to Alzheimer’s Disease Modification, Alzheimer’s Dement. source

  • It may state two separate claims as one.

    Premisecitation

    CT1812 is an orally delivered small molecule that penetrates the blood-brain barrier, binds selectively to S2R, is under development by Cognition Therapeutics, and is in Phase 2 clinical trials for Alzheimer's disease.

    “CT1812 is an orally delivered small molecule that penetrates the blood–brain barrier and binds selectively to S2R that is currently under development by Cognition Therapeutics, and in Phase 2 clinical trials for Alzheimer’s disease (NCT03507790, NCT04735536, NCT05531656).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites NCT03507790, NCT04735536, NCT05531656

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    Small molecule therapeutics targeting S2R have exhibited increasing success in amelioration of pathology observed in Alzheimer's disease, including restoration of membrane trafficking, synaptic plasticity, synaptic density, and memory ability, primarily via displacing the binding of toxic amyloid-β oligomers.

    “Small molecule therapeutics targeting S2R have exhibited increasing success in amelioration of pathology observed in Alzheimer’s disease, including restoration of membrane trafficking, synaptic plasticity, synaptic density, and memory ability, primarily via displacing the binding of toxic amyloid-β oligomers.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    Results from preclinical Alzheimer's models support that targeting S2R with a small-molecule approach may be a beneficial therapeutic strategy by displacing synaptotoxic amyloid-β oligomers, preventing synaptotoxicity, enabling synapses to recover, and slowing cognitive decline.

    “In sum, results from studies in preclinical Alzheimer’s models support that targeting S2R with a small-molecule approach may be a beneficial therapeutic strategy by displacing synaptotoxic amyloid-β oligomers, and preventing synaptotoxicity, thereby enabling synapses to recover and slow cognitive decline [2,3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Izzo, N.J., Staniszewski, A., To, L., Fa, M., Teich, A.F., Saeed, F., Wostein, H., Walko, T., Vaswani, A., and Wardius, M. (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. source
    • cites [3] Izzo, N.J., Xu, J., Zeng, C., Kirk, M.J., Mozzoni, K., Silky, C., Rehak, C., Yurko, R., Look, G., and Rishton, G. (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. source

  • It may state two separate claims as one.

    Premisecitation

    S2R (TMEM97) functions in close association with PGRMC1 and actuates its functions through the formation of protein-protein interactions, including a protein complex that binds oligomers and LDLR.

    “S2R (TMEM97) functions in close association with PGRMC1 and actuates its functions through the formation of protein–protein interactions, including a protein complex that binds oligomers and LDLR (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    S2R expression is elevated in retinal pigment epithelium-specific Clic4 knockout mice, which exhibit functional and pathological hallmarks of dry AMD; TMEM97 knockout mice have exhibited conflicting results in dry AMD models; and S2R-selective modulation with CM398 reduced photoreceptor loss and retinal autofluorescent granules in an illumination-induced AMD model.

    “S2R expression is elevated in retinal pigment epithelium-specific Clic4 knockout mice, which exhibit both functional and pathological hallmarks of dry AMD. Conversely, TMEM97 knockout mice have exhibited conflicting results in dry AMD models, which are likely dependent upon the type of stressor used to induce pathology. Intravenous administration of sodium iodate to TMEM97 knockout animals induced”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [119] Shen, 2021, TMEM97 Ablation Aggravates Oxidant-Induced Retinal Degeneration, Cell Signal. source
    • cites [73] Wang, 2022, Σ2R/TMEM97 in Retinal Ganglion Cell Degeneration, Sci. Rep. source
    • cites [84] Mavlyutov, T.A., Li, J., Liu, X., Shen, H., Yang, H., McCurdy, C.R., Pattnaik, B., and Guo, L.W. (2022). Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation. Genes, 13. source

  • It may state two separate claims as one.

    Premisecitation

    In preclinical studies, CT1812 slows amyloid-β oligomer-induced loss of synapses and restores synaptic activity.

    “In preclinical studies, CT1812 also slows amyloid-β oligomer-induced loss of synapses and restores synaptic activity (Figure 4) [64]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Izzo, 2021, Preclinical and Clinical Biomarker Studies of CT1812: A Novel Approach to Alzheimer’s Disease Modification, Alzheimer’s Dement. source

  • It may state two separate claims as one.

    Interpretationcitation

    Taken together, these data indicate that S2R function is important in dry AMD pathogenesis and in other retinopathies.

    “Taken together, these data indicate that S2R function is important in dry AMD pathogenesis and in other retinopathies.”
    Quote in the paperSubstantial claim
60 of 60

  • The paper relies on this without support.

    There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system.

    “There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system.”

  • The paper relies on this without support.

    The aberrant activity of S2R-mediated cellular processes is a hallmark of the dysfunction underlying degenerative diseases, including Alzheimer’s disease, α-synucleinopathies, and retinal diseases such as dry AMD.

    “The aberrant activity of S2R-mediated cellular processes, believed to be triggered by cellular stresses and exacerbated in aged cells, is a hallmark of the dysfunction underlying degenerative diseases, including Alzheimer’s disease, α-synucleinopathies, such as Parkinson’s disease and dementia with Lewy bodies, and retinal diseases, such as dry AMD.”

  • The paper relies on this without support.

    In α-synucleinopathies such as dementia with Lewy bodies and Parkinson’s disease, α-synuclein builds up in the brain and forms oligomers that saturably bind to neurons where they impair critical cellular processes, causing synaptic dysfunction and eventual loss.

    “In α-synucleinopathies such as dementia with Lewy bodies and Parkinson’s disease, α-synuclein builds up in the brain and forms oligomers that saturably bind to neurons where they impair critical cellular processes, causing synaptic dysfunction and eventual loss.”

  • The paper relies on this without support.

    Dry AMD remains a leading cause of blindness, and there are no approved therapies at present.

    “Dry AMD remains a leading cause of blindness, and there are no approved therapies at present.”

  • The paper relies on this without support.

    S2R is broadly expressed, but importantly is expressed in tissues relevant to age-related degenerative disorders of the central nervous system, including the brain and retina.

    “S2R is broadly expressed, but importantly is expressed in tissues relevant to age-related degenerative disorders of the central nervous system, including the brain and retina, and is intimately involved in regulating disease-relevant functions.”

  • The paper relies on this without support.

    The underlying cause of Huntington’s disease is the expansion of a CAG repeat in the huntingtin gene.

    “The underlying cause of Huntington’s disease is well-known to be the expansion of a CAG repeat in the huntingtin gene.”

  • The paper relies on this without support.

    Downstream of internalization, amyloid-β oligomers cause neuronal oxidative stress and dysfunction of autophagic and lysosomal vesicles.

    “Downstream of internalization, amyloid-β oligomers cause neuronal oxidative stress and dysfunction of autophagic and lysosomal vesicles.”
7 of 7

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.

  • Dry AMD described as having no approved treatment after an approval is reported

    Minor

    The paper says no therapeutics are FDA-approved to treat dry AMD, but later reports FDA approval of Syfovre for geographic atrophy secondary to dry AMD.

1 of 1

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Metadata

Authors
Lizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E.
Affiliations
  • Cognition Therapeutics (United States) (US)
  • IHS International, San Diego, CA92130, USA
  • University of California San Diego (US)
Corresponding author
Hamby, Mary E.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2023-03-26
Volume
24
Issue
7
Pages
6251
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms24076251
PMC
PMC10093856
OpenAlex
W4361007259
Semantic Scholar
4a491018277b7e99bfe43a0b7ad8162ace7d00d1
Cited by
54
References
187
Citations by year
2026: 9 · 2025: 20 · 2024: 19 · 2023: 6
FWCI
1.91
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Cognition Therapeutics, Inc.
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
sigma-2 receptor, TMEM97, PGRMC1, age-related degenerative diseases, central nervous system, Alzheimer's disease, synucleinopathies, dry age-related macular degeneration, autophagy, oxidative stress, amyloid-beta toxicity, small-molecule ligands, disease-modifying therapy, retinal cells
MeSH terms
Alzheimer Disease, Animals, Biology, Amyloid beta-Peptides, Receptors, sigma, Lewy Body Disease, alpha-Synuclein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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