Tau Proteins: Enabler of Diverse Neurodegenerative Diseases
Tau proteins stabilize microtubules in neuronal axons under normal conditions, but in pathological states, they undergo abnormal modifications like hyperphosphorylation, leading to insoluble aggregates that disrupt neuronal function. This results tau proteins in the pathogenesis of a range of neurodegenerative disorders such as Alzheimer's disease (AD), autism, and epilepsy, making them therapeutic targets for these tauopathies. Various therapeutic approaches target Tau, including small molecules, kinase inhibitors, immunotherapies, antisense oligonucleotides, and nanoparticle-based therapies.
SignalChem Biotech offers the largest recombinant Tau protein library, featuring diverse isoforms and phosphorylation states, optimized for biomarker assays. They have been used in biomedical research to study tauopathies, develop assays for detecting biomarkers like phosphorylated Tau217, and investigate the effects of Tau modifications on neuronal functions and injury models. This extensive collection provides researchers with reliable tools for studying Tau’s role in disease progression and advancing drug development.
Physiological and Pathological Roles of Tau Proteins
Under normal physiological conditions, Tau proteins help stabilize microtubules in neuronal axons, facilitating proper axonal transport and neuronal function. However, in pathological states, Tau proteins undergo abnormal post-translational modifications, such as hyperphosphorylation [1,2]. This results in the formation of insoluble Tau aggregates, which disrupt microtubule stability and lead to neuronal damage and dysfunction [2]. In Alzheimer's disease, the most well-known tauopathy, hyperphosphorylated Tau forms neurofibrillary tangles (NFTs), which are a hallmark of the disease [1,3]. These tangles interfere with neuronal communication and contribute to the progressive cognitive decline seen in Alzheimer's patients (Figure 1).
From Bench to Bedside
Various approaches have been pursued to target Tau proteins, aiming to mitigate their pathological effects in neurodegenerative diseases. These include the development of small molecule inhibitors (kinase inhibitors, Tau aggregation inhibitors, etc.), immunotherapies, antisense oligonucleotides (ASOs), and nanoparticle therapies [4–8]. These strategies are at different stages of research and clinical trials, offering hope for effective treatments for tauopathies such as Alzheimer's disease, autism, and epilepsy.
Application in Research
Recombinant Tau proteins from SignalChem Biotech have been utilized by researchers to study tauopathies. For instance, Eisenbaum et al. utilized recombinant biotin-labeled human Tau-441 (Cat#: T08-54BN, SignalChem) and DYRK1A-phosphorylated biotin-labeled human Tau (Cat#: T08-50RNB, SignalChem) for intracranial injection to mouse models of repetitive mild traumatic brain injury (r-mTBI) and used as a standard for ELISA assays. Authors observed elevated levels of exogenous Tau in the brain at 12 months post-injury compared to r-sham mice, indicating reduced Tau elimination (Figure 2) [9]. Gonzalez-Ortiz et al. developed a new assay for detecting phosphorylated Tau217 (p-Tau217), a promising emerging biomarker for Alzheimer's disease, using in vitro phosphorylated recombinant full-length Tau-441 (Cat#: T08-50FN, SignalChem) as the assay calibrator (Figure 3) [10]. Additionally, Dillon et al. found that adding human Tau significantly increased tubulin polymerization, but co-transfection with TTBK1 reduced this effect. Using recombinant human Tau co-expressed with TTBK1 in E. coli cells (Tau-441, TTBK1-phosphorylated, Cat#: T08-50ON, SignalChem), they confirmed that TTBK1-phosphorylated Tau impairs tubulin polymerization by reducing tau binding to microtubules (Figure 4) [11].
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References
1. Cummings, J. L. et al. The therapeutic landscape of tauopathies: challenges and prospects. Alzheimer’s Research and Therapy vol. 15 Preprint at https://doi.org/10.1186/s13195-023-01321-7 (2023).
2. Liu, X., Ye, M. & Ma, L. The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer’s disease. Frontiers in Aging Neuroscience vol. 14 Preprint at https://doi.org/10.3389/fnagi.2022.1022821 (2022).
3. Jadhav, S. et al. A walk through tau therapeutic strategies. Acta neuropathologica communications vol. 7 22 Preprint at https://doi.org/10.1186/s40478-019-0664-z (2019).
4. Aillaud, I. & Funke, S. A. Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease. Cellular and Molecular Neurobiology vol. 43 951–961 Preprint at https://doi.org/10.1007/s10571-022-01230-7 (2023).
5. Aljassabi, A., Zieneldien, T., Kim, J., Regmi, D. & Cao, C. Alzheimer’s Disease Immunotherapy: Current Strategies and Future Prospects. Journal of Alzheimer’s Disease vol. 98 755–772 Preprint at https://doi.org/10.3233/JAD-231163 (2024).
6. Yadikar, H. et al. Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. PLoS One 15, (2020).
7. Vemula, P., Schoch, K. M. & Miller, T. M. Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo. Front Mol Neurosci 16, (2023).
8. Muolokwu, C. E. et al. Functionalized nanoparticles to deliver nucleic acids to the brain for the treatment of Alzheimer’s disease. Frontiers in Pharmacology vol. 15 Preprint at https://doi.org/10.3389/fphar.2024.1405423 (2024).
9. Eisenbaum, M. et al. Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier. Fluids Barriers CNS 18, (2021).
10. Gonzalez-Ortiz, F. et al. A novel ultrasensitive assay for plasma p-tau217: Performance in individuals with subjective cognitive decline and early Alzheimer’s disease. Alzheimer’s and Dementia 20, 1239–1249 (2024).
11. Dillon, G. M. et al. Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites. PLoS One 15, (2020).