ArticleBrain : a journal of neurology2012
Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers.
Article in Brain : a journal of neurology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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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.
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Who cites it
49 citing papers in PubMed, 92 citations in OpenAlex.
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- Review
- Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.Frontiers in molecular biosciences · 2024Review
- Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.Pharmacological reviews · 2023Review
- Quantum-dot-labeled synuclein seed assay identifies drugs modulating the experimental prion-like transmission.Communications biology · 2022Article
- Three-repeat and four-repeat tau isoforms form different oligomers.Protein science : a publication of the Protein Society · 2022Article
- Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes.Communications biology · 2021Article
- The Molecular Tweezer CLR01 Inhibits Antibody-Resistant Cell-to-Cell Spread of Human Cytomegalovirus.Viruses · 2021Article
- The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.Alzheimer's research & therapy · 2021Article
- Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson's Disease.Frontiers in immunology · 2021Review
- Pharmacological Modulators of Tau Aggregation and Spreading.Brain sciences · 2020Review
- Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.Journal of the American Chemical Society · 2020Article
- CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.Nature communications · 2020Article
- Different Inhibitors of Aβ42-Induced Toxicity Have Distinct Metal-Ion Dependency.ACS chemical neuroscience · 2020Article
- The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Theoretical study on noncovalent interaction of molecular tweezers by Zn(II) salphen-azo-crown ether triads receptor.Journal of molecular modeling · 2020Article
- Glucose Overload Inhibits Glutamatergic Synaptic Transmission: A Novel Role for CREB-Mediated Regulation of Synaptotagmins 2 and 4.Frontiers in cell and developmental biology · 2020Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
Abstract
Alzheimer's disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer's disease-associated synaptotoxicity and reduce Alzheimer's disease-like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood-brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer's disease and related disorders.
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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.