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Under normal circumstances, tau is a microtubule-associated protein (MAP) involved in microtubule stabilization. However, it is also a multi-functional protein with a critical role in certain neurodegenerative disorders including Alzheimer's disease (AD)1.
The tau protein is highly soluble, expressed in neurons, oligodendrocytes, and astrocytes within the central nervous system (CNS) and peripheral nervous system (PNS)2,3.
It is primarily found in axons where it regulates microtubule polymerization and stabilization. However, its broad selection of binding partners suggest that it has multiple functions, including postnatal brain maturation, regulation of axonal transport and signaling cascades, cellular response to heat shock, and adult neurogenesis4.
Tau can be divided into four regions: an N-terminal region, a proline-rich domain, a microtubule-binding domain (MBD), and a C-terminal region5. The human tau gene (MAPT) contains 16 exons, and alternative splicing of exons 2, 3, and 10 yields six isoforms (see Figure 1).
The tau protein contains 85 potential serine (S), threonine (T), and tyrosine (Y) phosphorylation sites, and under normal conditions phosphorylation helps to maintain cytoskeletal structure6,7. Abnormal phosphorylation of tau is known to contribute to AD pathology, with approximately 45 specific phosphorylation sites identified in the AD brain6,8.
Tau is subject to multiple post-translational modifications in addition to phosphorylation, including glycosylation, glycation, truncation, nitration, oxidation, polyamination, ubiquitination, sumoylation and aggregation9.
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.
Alzheimer’s disease is the most common form of dementia and is characterized by extracellular amyloid beta (Aβ) plaques, and intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau10. Aβ senile plaques and NFTs are both formed of insoluble, densely-packed filaments.
Accumulation of plaques and NFTs is correlated with AD symptoms and results in neuron damage and death11. It is now believed that soluble Aβ and tau work in tandem, independently of their accumulation into plaques and tangles, to push neurons towards a diseased state11.
In Alzheimer’s disease, elevation of intracellular soluble Aβ leads to the abnormal phosphorylation of tau and its release from microtubules in a soluble monomeric form6,12. In response to Aβ, tau is relocated from axons to the somatodendritic compartments of neurons12. Here, tau is able to bind and sequester the Src tyrosine kinase, fyn, altering its localization13.
Elevated levels of fyn accompany the elevated levels of tau in dendritic spines, allowing the phosphorylation and stabilization of excitatory GluN2B NMDA receptors. This enhances glutamate signaling and causes an intracellular flood of Ca2+, which enhances Aβ toxicity11,13,14. Calcium-induced excitotoxicity can damage post-synaptic sites and cause mitochondrial Ca2+ overload, membrane depolarization, oxidative stress and apoptotic cell death7,11,15,16.
Extracellular vesicles may be involved in the dissemination of pathological Aβ and tau in a prion-like propagation of AD plagues and NFTs17,18.
Novel therapeutic strategies for the treatment of AD may include preventing the Aβ-induced, tau-dependent enhancement of NMDA receptor activity, by reducing dendritic levels of fyn19 or targeting tau directly20.
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).