Role of Tau Protein in Alzheimer's Disease

This article provides a brief overview of the tau protein and how it plays a role in Alzheimer's disease.


The tau protein has dual functions. Under normal conditions, it acts as a microtubule-associated protein (MAP) that plays a role in microtubule stabilization, but in certain neurodegenerative disorders such as Alzheimer's disease, (AD) it becomes a multi-functional protein with a significant role1.

The highly soluble tau protein is expressed in astrocytes, oligodendrocytes and neurons within the central nervous system (CNS) as well as the peripheral nervous system (PNS)2,3. The tau protein is predominantly present in axons, where it controls the polymerization and stabilization of microtubules.

Yet, considering its wide selection of binding partners, this protein is believed to have multiple functions such as postnatal brain maturation, adult neurogenesis, cellular response to heat shock, and regulation of axonal transport and signaling cascades4.


The tau protein can be divided into four regions:

  • N-terminal region
  • proline-rich domain
  • microtubule-binding domain (MBD)
  • C-terminal region5

Figure 1 shows the human tau gene (MAPT) that contains 16 exons as well as alternative splicing of exons 2, 3, and 10 yields six isoforms.


Figure 1. Alternative splicing of tau produces isoforms ranging in length from 352 to 441 amino acids. Exons 2 and 3 of the tau gene encode two N terminal inserts (N1 and N2). Absence of exons 2 and 3 gives rise to 0N tau isoforms, inclusion of exon 2 results in 1N isoforms and inclusion of both exons 2 and 3 produces 2N isoforms. R1–R4 represent the four microtubule-binding domains with R2 being encoded by exon 10. Inclusion of exon 10 results in 4R isoforms, whilst exclusion results in 3R isoforms.

Tau contains 85 potential threonine (T), serine (S) and tyrosine (Y) phosphorylation sites. Under normal circumstances, cytoskeletal structure is maintained by phosphorylation6,7. When tau undergoes abnormal phosphorylation, it contributes to the pathology of Alzheimer's disease with about 45 specific phosphorylation sites detected in the Alzheimer's brain6,8.

Besides phosphorylation, tau is also subject to many post-translational modifications such as glycation, glycosylation, nitration, truncation, polyamination, oxidation, sumoylation, ubiquitination and aggregation9.

Role in Alzheimer's disease

Being the most common form of dementia, Alzheimer’s disease is characterized by extracellular amyloid beta (Aβ) plaques as well as intracellular neurofibrillary tangles (NFTs) that consist of hyperphosphorylated tau10. Both NFTs and Aβ senile plaques are formed of densely-packed, insoluble filaments.

The buildup of NFTs and plaques is associated with Alzheimer’s symptoms and leads to damage and death of neurons11. The soluble Aβ and tau are believed to work together independent of their accumulation into tangles and plaques, driving neurons towards a diseased state11.

In Alzheimer’s disease, increased levels of intracellular soluble Aβ cause abnormal phosphorylation of tau protein and its subsequent release from microtubules in a form of soluble monomer6,12. The tau protein is relocated from axons to the neuron’s somatodendritic compartments, in response to Aβ plagues 12. Here, the tau protein alters the localization of Src tyrosine kinase, fyn, by binding and sequestering it13.

In dendritic spines, increased levels of fyn are associated with increased levels of tau enabling the excitatory GluN2B NMDA receptors to be phosphorylated and stabilized. As a result, the glutamate signaling is improved promoting an intracellular flood of Ca2+, which in turn improves the toxicity of Aβ11,13,14.

Excitotoxicity induced by calcium can damage post-synaptic sites and lead to mitochondrial Ca2+ overload, oxidative stress, membrane depolarization and apoptotic cell death7,11,15,16.

It is believed that extracellular vesicles are involved in the dissemination of pathological tau and Aβ in a prion-like propagation of NFTs and Alzheimer’s plagues17,18.

New therapeutic approaches for Alzheimer’s treatment may include prevention of tau-dependent, Aβ-induced improvement of NMDA receptor activity through reduction of dendritic fyn levels19 or direct targeting of the tau protein20.

Recommended tools for studying Tau protei

  • Anti-Tau antibody [TAU-5] - BSA and Azide free
  • Anti-Tau (phospho S396) antibody [EPR2731]
  • Anti-Tau (phospho S262) antibody
  • Anti-Tau (phospho T231) antibody [EPR2488]
  • Anti-Tau (phospho S422) antibody [EPR2866]
  • Anti-Tau (phospho S404) antibody [EPR2605]
  • Anti-Tau (phospho S199) antibody [EPR2401Y]
  • Anti-Tau (phospho S356) antibody [EPR2603]
  • Anti-Tau (phospho S202) antibody [EPR2402]
  • Anti-Tau (phospho T205) antibody
  • Anti-Tau (phospho S202 + T205) antibody [EPR20390]


  1. Ballatore, C., Lee, V. M.-Y. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).
  2. Gu, Y., Oyama, F. & Ihara, Y. Tau is widely expressed in rat tissues. J. Neurochem. 67, 1235–1244 (1996).
  3. Trojanowski, J. Q., Schuck, T., Schmidt, M. L. & Lee, V. M. Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem 37, 209–215 (1989).
  4. Morris, M., Maeda, S., Vossel, K. & Mucke, L. The Many Faces of Tau. Neuron 70, 410–426 (2011).
  5. Mandelkow, E. M. et al. Structure, microtubule interactions, and phosphorylation of tau protein. Ann. N. Y. Acad. Sci. 777, 96–106 (1996).
  6. Noble, W., Hanger, D. P., Miller, C. C. J. & Lovestone, S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol. 4, 1–11 (2013).
  7. Danysz, W. & Parsons, C. G. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine - searching for the connections. Br. J. Pharmacol. 167, 324–352 (2012).
  8. Gong, C.-X. & Iqbal, K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr. Med. Chem. 15, 2321–8 (2008).
  9. Martin, L., Latypova, X. & Terro, F. Post-translational modifications of tau protein: Implications for Alzheimer’s disease. Neurochem. Int. 58, 458–471 (2011).
  10. 10. Tanzi, R. E. & Bertram, L. Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective. Cell 120, 545–555 (2005).
  11. Bloom, G. S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–8 (2014).
  12. Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E.-M. Abeta Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines. J. Neurosci. 30, 11938–11950 (2010).
  13. Haass, C. & Mandelkow, E. Fyn-tau-amyloid: a toxic triad. Cell 142, 356–8 (2010).
  14. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).
  15. Alberdi, E. et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47, 264–72 (2010).
  16. Bieschke, J. et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils. Nat. Chem. Biol. 8, 93–101 (2012).
  17. Vingtdeux, V., Sergeant, N. & Buée, L. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front. Physiol. 3, 229 (2012).
  18. Frost, B. & Diamond, M. I. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159 (2010).
  19. Nygaard, H. B., van Dyck, C. H. & Strittmatter, S. M. Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimers. Res. Ther. 6, 8 (2014).
  20. Murray, M. E. et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain 138, 1370–81 (2015)

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Last updated: Feb 5, 2018 at 5:25 AM

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