Tau Protein: A Key Player and Therapeutic Target in Alzheimer's Disease
Tau protein is a microtubule-associated protein predominantly found in neurons, playing a crucial role in maintaining cellular cytoskeletal stability and neuronal function. However, when Tau protein undergoes abnormal modifications (such as hyperphosphorylation), it forms neurofibrillary tangles (NFTs), which are the hallmark pathological features of Alzheimer's disease (AD) and other tauopathies.
- Recent Advances
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Maintaining Microtub StabilityuleTau protein binds to tubulin (α/β-tubulin), promoting microtubule assembly and enhancing its structural stability. This is essential for axonal transport (such as the directional transport of mitochondria, vesicles, and nutrients). Different splice isoforms (such as 3R-Tau and 4R-Tau) regulate microtubule dynamics through the microtubule-binding domain (MTBD).
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Regulating Neuronal Morphology and PlasticityTau protein is involved in synapse formation and function maintenance, affecting neurotransmitter release and synaptic plasticity (such as-term long potentiation, LTP). During development, changes in Tau protein expression levels are closely related to neuronal migration and axonal growth.
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Signal Transduction and Cellular ProtectionTau protein interacts with kinases (such as GSK-3β, CDK5) and phosphatases (such as PP2A), participating in cell survival and apoptosis signaling pathways. Recent studies have found that Tau may also regulate gene expression by binding to DNA or RNA.
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Disruption of Microtubule Stability and Axonal Transport ImpairmentHyperphosphorylated Tau protein detaches from microtubules, leading to microtubule disassembly, which obstructs axonal transport and causes synaptic dysfunction and neuronal energy depletion.
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Formation of Neurofibrillary Tangles (NFTs)Misfolded Tau proteins aggregate to form insoluble fibrous aggregates (such as paired helical filaments, PHF, and straight filaments, SF), which constitute the core components of NFTs. NFTs deposit within neurons, eventually leading to cell death and the release of pathological Tau into the extracellular space, which can spread within the brain through a "prion-like" mechanism.
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Synaptic Toxicity and NeuroinflammationSoluble Tau oligomers (rather than mature NFTs) can directly impair synaptic function, inhibit long-term potentiation (LTP), and affect memory formation. NFTs activate microglia and astrocytes, releasing pro-inflammatory cytokines (such as IL-6, TNF-α), which exacerbate neurodegenerative changes.
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Synergistic Effects with Other Pathological ProteinsIn Alzheimer's disease (AD), Tau pathology interacts with β-amyloid (Aβ) ("Aβ-Tau hypothesis"): Aβ may trigger Tau hyperphosphorylation, while Tau pathology drives disease progression to the late stages.
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Alzheimer's Disease (NFTs and β-amyloid plaques together form the pathological core).
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Primary Tauopathies: Such as frontotemporal lobar degeneration (FTLD-Tau), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).
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Inhibiting Tau Hyperphosphorylation: Such as kinase inhibitors (targeting GSK-3β, CDK5, etc.).
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Reducing Tau Aggregation: Small molecule compounds (such as methylene blue derivative LMTM) or antibodies targeting pathological Tau for clearance.
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Enhancing Tau Clearance: Through activation of autophagy or the ubiquitin-proteasome system.
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Gene Therapy: Such as antisense oligonucleotides (ASOs) to reduce Tau expression.
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Immunotherapy: Clinical trials of anti-Tau antibodies (such as AADvac1, semorinemab) are ongoing.
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Disease Heterogeneity: Different Tauopathies have distinct Tau isoform distributions, requiring personalized strategies.
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Blood-Brain Barrier Penetration: Delivery efficiency issues with large molecule drugs (such as antibodies).
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Biomarker Development: Detection of Tau protein in blood or cerebrospinal fluid (such as p-Tau181, p-Tau217) still needs optimization.
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Recombinant Tau Protein Products |
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Expression Host : E.coli |
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Expression Host : CHO |
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Expression Host : E.coli |
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Tau Antibody Products |
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Tau (phospho T217) Recombinant Rabbit mAb (SDT-R205-TT217-4) |
Source : Rabbit |
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Partial Data Sharing:
Tau-441/2N4R His Tag Protein, Human （UA030093）
Immobilized Tau-441/2N4R His Tag Protein, Human at 2 μg/mL (100 μL/well) can bind Tau Recombinant Rabbit mAb (SDT-171-67) (Cat. No. S0B0036) with EC50 of 7.3-10.1 ng/mL.
Recommended Pairings:
References:
- Jonathan Gallego-Rudolf; Alex I. Wiesman; Alexa Pichet Binette; Sylvia Villeneuve; Sylvain Baillet.Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.Nature Neuroscience.2024.
- C Bravo; Sarah Naguib; Li Gan. Cellular and pathological functions of tau. Nature Reviews Molecular Cell Biology.2024.
- Novak, P. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat. Aging 1.2021.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/.NCT04445831 .
- Tai, C.-Y. et al. APNmAb005, an anti-tau antibody targeting synaptic tau oligomers, in phase 1 for treatment of Alzheimer’s Disease and primary tauopathies. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04867616 .
- Zhou, J. et al. E2814: an anti-tau therapy engages its CNS target and afects the downstream tangle-specific biomarker MTBR-tau243 in dominantly inherited Alzheimer’s disease. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04619420 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04149860 .2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05466422 .
- Luca, W., Foster, K., McClure, K., Ahlijanian, M. K. & Jefson, M. A phase 1 single-ascendingdose trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous PNT001, a novel mid-domain tau antibody targeting cis-pT231 tau. J. Prev. Alzheimers Dis. 2024.
- Martenyi, F. et al. PRX005, a novel anti-MTBR tau monoclonal antibody: results from a first-in-human double-blind, placebo-controlled, single ascending dose phase 1 study. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03828747.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04759365.
- Permanne, B. et al. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem. Neurosci. 2022.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05195008.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03706885 .
- Verwaerde, P. et al. First-in-human safety, tolerability, and pharmacokinetics of single and multiple doses of AZP2006, a synthetic compound for the treatment of Alzheimer’s disease and related diseases. J. Alzheimers Dis. 2024.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04685590 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03446001.
- Yipeng Wang; Eckhard Mandelkow.Tau in physiology and pathology.Nature Reviews Neuroscience.2015.
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- Jonathan Gallego-Rudolf; Alex I. Wiesman; Alexa Pichet Binette; Sylvia Villeneuve; Sylvain Baillet.Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.Nature Neuroscience.2024.
- C Bravo; Sarah Naguib; Li Gan. Cellular and pathological functions of tau. Nature Reviews Molecular Cell Biology.2024.
- Novak, P. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat. Aging 1.2021.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/.NCT04445831 .
- Tai, C.-Y. et al. APNmAb005, an anti-tau antibody targeting synaptic tau oligomers, in phase 1 for treatment of Alzheimer’s Disease and primary tauopathies. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04867616 .
- Zhou, J. et al. E2814: an anti-tau therapy engages its CNS target and afects the downstream tangle-specific biomarker MTBR-tau243 in dominantly inherited Alzheimer’s disease. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04619420 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04149860 .2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05466422 .
- Luca, W., Foster, K., McClure, K., Ahlijanian, M. K. & Jefson, M. A phase 1 single-ascendingdose trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous PNT001, a novel mid-domain tau antibody targeting cis-pT231 tau. J. Prev. Alzheimers Dis. 2024.
- Martenyi, F. et al. PRX005, a novel anti-MTBR tau monoclonal antibody: results from a first-in-human double-blind, placebo-controlled, single ascending dose phase 1 study. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03828747.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04759365.
- Permanne, B. et al. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem. Neurosci. 2022.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05195008.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03706885 .
- Verwaerde, P. et al. First-in-human safety, tolerability, and pharmacokinetics of single and multiple doses of AZP2006, a synthetic compound for the treatment of Alzheimer’s disease and related diseases. J. Alzheimers Dis. 2024.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04685590 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03446001.
- Yipeng Wang; Eckhard Mandelkow.Tau in physiology and pathology.Nature Reviews Neuroscience.2015.
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