ArticlePloS one2014
Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
113 citing papers in PubMed, 1 synthesis or guideline pooled it, 302 citations in OpenAlex.
- CT1812 biomarker signature from a meta-analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Pooled it
- Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.Alzheimer's research & therapy · 2026Trial
- A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer's Disease.The journal of prevention of Alzheimer's disease · 2024Trial
- Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2021Trial
- Crystal Structure of the Sigma‑2 Receptor Complexed with Investigational Drug Zervimesine (CT1812).ACS medicinal chemistry letters · 2026Article
- CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice.Neurochemical research · 2026Article
- Patient perspectives on sexual orientation and gender identity data collection in cancer care settings.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2026Article
- Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.Experimental neurobiology · 2026Review
- From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.bioRxiv : the preprint server for biology · 2026Article
- Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.The Journal of pharmacology and experimental therapeutics · 2026Article
- Sigma‑2 Receptor/Transmembrane Protein 97 in Pain Modulation: Tracing Historical Roots and Current Research Directions.ACS pharmacology & translational science · 2025Review
- Neurosteroids Progesterone and Dehydroepiandrosterone: Molecular Mechanisms of Action in Neuroprotection and Neuroinflammation.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Discovery of Iboga-Derived Ligands for the Sigma‑2 Receptor.ACS bio & med chem Au · 2025Article
- A Review of the Clinical Progress of CT1812, a Novel Sigma-2 Receptor Antagonist for the Treatment of Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Sigma-2 receptor modulator CT1812 alters key pathways and rescues retinal pigment epithelium (RPE) functional deficits associated with dry age-related macular degeneration (AMD).Scientific reports · 2025Article
- Advances in synaptic PET imaging and intervention with synapse-targeted small-molecular drugs for dementia diagnosis and therapy.Fundamental research · 2025Review
- Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.Frontiers in neuroscience · 2025Review
- Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.Antioxidants (Basel, Switzerland) · 2024Article
- Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons.Frontiers in aging neuroscience · 2024Review
- Modeling Alzheimer's disease using human cell derived brain organoids and 3D models.Frontiers in neuroscience · 2024Review
53 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 8 institutions in 3 countries.
Funding
Abstract
Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.