ArticleBrain : a journal of neurology2024
New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.
Article in Brain : a journal of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.Free radical biology & medicine · 2026Article
- α/Sulfonyl-γ-AApeptide foldamers mitigate Alzheimer's disease pathology by stabilizing transient helical domains in Aβ.Nature communications · 2026Article
- Identification of RPL4 as a biomarker associated with disulfidptosis and arachidonic acid metabolism in breast cancer.Discover oncology · 2026Article
- Obesity-driven phosphatidylethanolamine dysregulation impairs neuroimmune crosstalk and accelerates Alzheimer's pathogenesis.Molecular neurodegeneration · 2026Article
- APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction.Cell death & disease · 2026Article
- Isothiocyanate-mediated cyclization of phage-displayed peptides enables discovery of macrocyclic binders.Science advances · 2026Article
- APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.Free radical biology & medicine · 2026Article
- Article
- Genetic Deletion of Cyclophilin D Results in Enhanced Hypoxia Tolerance in Mice.Cellular and molecular neurobiology · 2026Article
- Mitochondrial oxidative stress promotes the accumulation of advanced glycation end products.PloS one · 2026Article
- Cyclophilin D suppresses colorectal cancer progression through the activation of an autophagy-mediated apoptotic pathway.Scientific reports · 2025Article
- Cyclophilin D reduces Ca2+ sequestration by complement 1q binding protein.The Biochemical journal · 2025Article
- Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2025Review
- A mitochondrial permeability transition-associated lncRNA signature predicts prognosis and the immune response in gastric cancer.Hereditas · 2025Article
- Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.Neurobiology of disease · 2025Article
- Glucocorticoids regulate small extracellular vesicle (sEV) release via activation of nSMase2.bioRxiv : the preprint server for biology · 2025Article
- Membrane sensitization biosensor based on magnetic inducing for Tau protein detection.Mikrochimica acta · 2025Article
- New Approaches to the Treatment of Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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Authors and funding
13 authors at 6 institutions in 1 country.
Funding
Abstract
Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
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