Geon 5. The Tau Protein Alzheimer

Tau is one of several types of microtubule-associated proteins (MAPs), responsible for the assembly and stability of microtubule networks. Although microtubule networks exist in all kinds of animal and plant cells, Tau is present only in neurons and predominantly localized in axons.

Tau is a major component of neurofibrillary tangles. It has been found that most Tau proteins in the tangles are hyperphosphorylated, suggesting that hyperphosphorylation of Tau may play an important role in Alzheimer's disease (AD). Phosphorylation is a process that adds a phosphate group (PO43−) to a protein, particularly on the amino acid serine, threonine or tyrosine. In an AD brain, too many residues in the Tau protein are phosphorylated.

Tau Isoforms


Figure 5-1. The gene, mRNA and protein isoforms of Tau. In Tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of Tau in adult human brain. Six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of Tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or repeats (coded by exons 9, 10, 11 and 12). The second repeat coded by exon 10 is highlighted by dark box. An isoform is commonly designated as xNyR, where x is the number of inserts and y is the number of repeats. [Source: Liu and Gong, 2008]

Tau has six isoforms produced from a single gene through alternative RNA splicing (Figure 5-1). They differ in the number of inserts at the N-terminal half and the number of repeats at the C-terminal half . The number of inserts may be 0, 1 or 2, depending on whether the exon 2 and/or 3 are included during RNA splicing. The number of repeats may be either 3 or 4. The 4-repeat (4R) Tau includes the second repeat encoded by exon 10.

The repeat region is the microtubule binding domain. The 4R Tau binds to, assembles, and stabilizes microtubules more effectively than 3R Tau (Bunker et al., 2004). In a healthy adult brain, the levels of 4R and 3R Tau proteins are approximately equal. Distortion of the balance toward 4R Tau will lead to neurodegeneration such as Alzheimer's disease and Huntington's disease (see Chapter 10).

Phosphorylation Sites

The longest isoform of Tau contains more than 60 potential phosphorylation sites. Among them, five are tyrosine residues, which exist in all isoforms. They are located at 18, 29, 197, 310 and 394 (numbering is based on the longest isoform). The tyrosine kinase Fyn preferentially targets tyrosine-18 (Y18), which is phosphorylated in the AD brain and at early developmental stages in mice, but not in healthy adult. Phosphorylation of Y18 does not significantly alter the microtubule binding (Lee et al., 2004), consistent with its location at the projection domain which may bind to other components such as the plasma membrane.

Another tyrosine residue, Y394, is also phosphorylated in both AD brain and fetal brain. The phosphorylation has little effect on microtubule binding. Unlike Y18, Y394 is targeted by tyrosine kinase c-Abl (Derkinderen et al., 2005). The finding that these residues are phosphorylated in fetus indicates that their phosphorylation has normal functions during development. In fact, it has been known for many years that Tau is highly phosphorylated in the fetal brain, but minimally phosphorylated in the healthy adult brain (Augustinack et al., 2002).

In the tangles, many serine and threonine residues are phosphorylated (Hanger et al., 1998). Among them, S262, S293, S324, and S356 are in the repeats; S199, S202, T205, T212, S214, T231 and S235 before the repeats; S396, S404 and S422 after the the repeats. Phosphorylation at these sites tends to disrupt the association between Tau and microtubule. Interestingly, phosphorylation at S199, S202, T205, S396 or S404 also reduces the association between Tau and the plasma membrane (Arrasate et al., 2000; Maas et al., 2000; Pooler et al., 2012).