ArticleHuman molecular genetics2021
Protective effects of a small molecule inhibitor ligand against hyperphosphorylated tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- RNA acetylation modification ac4C: An emerging regulatory hub of RNA metabolism disruption in Alzheimer's disease.Molecular biology reports · 2026Review
- Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular Docking Studies Targeting Toxic Polyglutamine (PolyQ) Repeats in Huntington's Disease.Current drug targets · 2026Article
- Molecular Modeling Insights on the Pharmaceuticals and Hypotheses of Alzheimer's Disease.Current medicinal chemistry · 2025Review
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- Peroxiredoxin 1 inhibits streptozotocin-induced Alzheimer's disease-like pathology in hippocampal neuronal cells via the blocking of CaScientific reports · 2024Article
- Amyloid-β and Phosphorylated Tau are the Key Biomarkers and Predictors of Alzheimer's Disease.Aging and disease · 2024Review
- Research progress of natural products and their derivatives against Alzheimer's disease.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- Genetically Engineered TripleCells · 2023Article
- Regulation of retinoid mediated StAR transcription and steroidogenesis in hippocampal neuronal cells: Implications for StAR in protecting Alzheimer's disease.Biochimica et biophysica acta. Molecular basis of disease · 2023Article
- Role of the Cysteine in R3 Tau Peptide in Copper Binding and Reactivity.International journal of molecular sciences · 2022Article
- Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.Human molecular genetics · 2022Article
- Structural Analysis and Conformational Dynamics of Short Helical Hyperphosphorylated Segments of Tau Protein (Sequence 254-290) in Alzheimer's Disease: A Molecular Dynamics Simulation Study.Frontiers in molecular biosciences · 2022Article
- Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.Pharmacological research · 2021Article
- Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer's Disease.International journal of molecular sciences · 2021Review
- Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline.Journal of Alzheimer's disease : JAD · 2021Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
The purpose of our study is to understand the protective effects of small molecule ligands for phosphorylated tau (p-tau) in Alzheimer's disease (AD) progression. Many reports show evidence that phosphorylated tau is reported to be an important contributor to the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in AD neurons. In AD, glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase-5 and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), are the three important kinases responsible for tau hyperphosphorylation. Currently, there are no drugs and/or small molecules that reduce the toxicity of phosphorylated tau in AD. In the present study, we rationally selected and validated small molecule ligands that bind to the phosphorylated tau at SER23 (Ser 285) and TYR44 (Tyr310). We also assessed the molecular dynamics and validated molecular docking sites for the three best ligands. Based on the best docking scores -8.09, -7.9 and -7.8 kcal/mol, we found that ligand 1 binds to key hyperphosphorylation residues of phosphorylated tau that inhibit abnormal PHF-tau, DYRK1A and GKS3β that reduce phosphorylated tau levels in AD. Using biochemical, molecular, immunoblotting, immunofluorescence and transmission electron microscopy analyses, we studied the ligand 1 inhibition as well as mitochondrial and synaptic protective effects in immortalized primary hippocampal neuronal (HT22) cells. We found interactions between NAT10-262501 (ligand 1) and phosphorylated tau at key phosphorylation sites and these ligand-based inhibitions decreased PHF-tau, DYRK1A and GSK3β levels. We also found increased mitochondrial biogenesis, mitochondrial fusion and synaptic activities and reduced mitochondrial fission in ligand 1-treated mutant tau HT22 cells. Based on these results, we cautiously conclude that phosphorylated tau NAT10-262501 (ligand 1) reduces hyperphosphorylation of tau based GKS3β and CDK5 kinase regulation in AD, and aids in the maintenance of neuronal structure, mitochondrial dynamics and biogenesis with a possible therapeutic drug target for AD.
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