ArticleActa neuropathologica communications2018
A new TAO kinase inhibitor reduces tau phosphorylation at sites associated with neurodegeneration in human tauopathies.
Article in Acta neuropathologica communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- The role of microRNAs in understanding sex-based differences in Alzheimer's disease.Biology of sex differences · 2024Pooled it
- Discovery of VU6083859, a TAOK1 Selective Inhibitor, and VU6080195, aACS chemical neuroscience · 2026Article
- Article
- Elevated Levels of Extracellular Vesicle-Associated TAOK1 in Plasma: A Diagnostic Marker for Cognitive Decline in Parkinson's Disease Dementia and Alzheimer's Disease.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- TAOK2 drives opposing cilia length deficits in 16p11.2 deletion and duplication carriers.Stem cell reports · 2025Article
- Novel strategies for targeting tau oligomers in neurodegenerative diseases.Journal of neurology · 2025Review
- Alzheimer's Disease and Frontotemporal Dementia: A Review of Pathophysiology and Therapeutic Approaches.Journal of neuroscience research · 2025Review
- Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions.Neurobiology of disease · 2025Article
- Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Biomarkers and Target-Specific Small-Molecule Drugs in Alzheimer's Diagnostic and Therapeutic Research: From Amyloidosis to Tauopathy.Neurochemical research · 2024Review
- Tau-mediated synaptic dysfunction is coupled with HCN channelopathy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- A novel monoclonal antibody generated by immunization with granular tau oligomers binds to tau aggregates at 423-430 amino acid sequence.Scientific reports · 2024Article
- Phosphoproteome Microarray Analysis of Extracellular Particles as a Tool to Explore Novel Biomarker Candidates for Alzheimer's Disease.International journal of molecular sciences · 2024Article
- Pleiotropic functions of TAO kinases and their dysregulation in neurological disorders.Science signaling · 2024Review
- Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies.Molecular neurodegeneration · 2023Review
- Article
- Prion-like strain effects in tauopathies.Cell and tissue research · 2023Review
- Neurodevelopmental disorder-associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase.Science signaling · 2023Article
- Analyzing alternative splicing in Alzheimer's disease postmortem brain: a cell-level perspective.Frontiers in molecular neuroscience · 2023Article
- A zebrafish pparγ gene deletion reveals a protein kinase network associated with defective lipid metabolism.Functional & integrative genomics · 2022Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
In Alzheimer's disease (AD) and related tauopathies, the microtubule-associated protein tau is highly phosphorylated and aggregates to form neurofibrillary tangles that are characteristic of these neurodegenerative diseases. Our previous work has demonstrated that the thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro. Here we show that TAOKs are phosphorylated and active in AD brain sections displaying mild (Braak stage II), intermediate (Braak stage IV) and advanced (Braak stage VI) tau pathology and that active TAOKs co-localise with both pre-tangle and tangle structures. TAOK activity is also enriched in pathological tau containing sarkosyl-insoluble extracts prepared from AD brain. Two new phosphorylated tau residues (T123 and T427) were identified in AD brain, which appear to be targeted specifically by TAOKs. A new small molecule TAOK inhibitor (Compound 43) reduced tau phosphorylation on T123 and T427 and also on additional pathological sites (S262/S356 and S202/T205/S208) in vitro and in cell models. The TAOK inhibitor also decreased tau phosphorylation in differentiated primary cortical neurons without affecting markers of synapse and neuron health. Notably, TAOK activity also co-localised with tangles in post-mortem frontotemporal lobar degeneration (FTLD) brain tissue. Furthermore, the TAOK inhibitor decreased tau phosphorylation in induced pluripotent stem cell derived neurons from FTLD patients, as well as cortical neurons from a transgenic mouse model of tauopathy (Tau35 mice). Our results demonstrate that abnormal TAOK activity is present at pre-tangles and tangles in tauopathies and that TAOK inhibition effectively decreases tau phosphorylation on pathological sites. Thus, TAOKs may represent a novel target to reduce or prevent tau-associated neurodegeneration in tauopathies.
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