The human tau gene extends over 100 kb on chromosome 17q21 and contains 16 exons. Restriction analysis and gene sequencing showed that it contains one CpG island associated with the promoter region, and another associated with exon 9. The CpG island in the former region resembles those described in neuron-specific promoters [21-24]. The sequence of this region is TATA-less which indicates that it is likely to contain multiple initiation sites, as is typical of housekeeping genes [22]. Three SP1 (specificityprotein 1)-binding sites that are important in directing transcription initiation in other TATA-less promoters are present in the proximity of the first transcription initiation site. The SP1-binding sites have been suggested to control neuronal specific expression of tau [12,21-24].

Three exons [4A, 6 and 8] are missing in the tau primary transcript expressed in the human brain and are specific to peripheral tau proteins. Exon 4A occurs in bovine, human and rodent peripheral tissues with a high degree of homology [22]. Exon –1 (minus one) is part of the promoter and is transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12 and 13 are constitutive exons. Exon 14 is part of the 3’UTR of tau mRNA. Exons 2, 3 and 10 are alternatively spliced and are adult brain-specific [21]. Exon 3 never appears independently of exon 2. Thus, alternative splicing of these three exons allows for six combinations (2-3-10-; 2+3-10-; 2+3+10-; 2-3-10+; 2+3-10+; 2+3+10+) so that in the human brain, the tau primary transcript gives rise to six mRNAs (Fig.1) [21,22,25].

The human brain tau isoforms contain from 352 to 441 amino acids (molecular mass from 45 to 65 kDa). They differ by the presence of either three (3R) or four (4R) repeat regions in the carboxy-terminal end and the absence or presence of one or two inserts (29 or 58 amino acids, respectively) in the aminoterminal end [12]. Since the isoforms are differentially expressed during development, each is likely to have a particular physiological role [12,21]. Only one, characterized by 3R and no amino-terminal inserts, is present during fetal stages, but all six isoforms are expressed during adulthood. Their specific functions may be related to the absence or presence of regions encoded by exons 2, 3 and 10 [21,26], and the isoforms may not be equally expressed in neurons. For instance, tau mRNAs containing exon 10 are not found in granular cells of the dentate gyrus. Thus, tau isoforms may be differentially distributed in neuronal subpopulations [12,21,26,27].

The presence or absence of 29 amino acid sequences encoded by exons 2 and 3 determine the length of the amino-terminal part of tau proteins [21]. These inserts are highly acidic and are followed by a basic proline-rich region (Fig. 2). The amino-terminal region is referred to as the projection domain, since it projects from the microtu bule surface where it may interact with other cytoskeletal elements and with the plasma membrane [28]. In fact, projection domains of tau determine spacings between microtubules in an axon and may increase axonal diameter. In peripheral neurons, which often project a very long axon with a large diameter, an additional amino-terminal sequence encoded by exon 4A is present, producing the specific isoform called “big tau” [21,27,28].

Tau proteins bind to spectrin and actin filaments. Through these interactions, they may allow microtubules to interconnect with other cytoskeletal components, such as neurofilaments. There is evidence that tau also interacts with cytoplasmic organelles and the Tau proteins bind to microtubules through the repeat domains (R1, R2, R3 and R4) encoded by exons 9-12 in their carboxy-terminal region. The 3R or 4R copies of a highly conserved 18-amino acid repeat are separated from each other by less conserved 13- or 14-amino acid inter-repeat domains. Tau proteins act as promoters of tubulin polymerization in vitro, and are involved in axonal transport [29]. The 18-amino acid repeats bind to microtubules through a variety of weak interactions. Adult tau isoforms with 4R are more efficient at promoting microtubule assembly than the fetal isoform with 3R [21,29]. The most potent in inducing microtubule polymerization is the inter-region between R1 and R2 which is unique to 4R-tau. Recent evidence supports a role for the microtubule-binding domain in the modulation of the phosphorylation state of tau proteins [21,30].

Posttranslational Modifications in Tau Proteins. One posttranslational modification observed in the tau protein is O-glycosylation [32]. The number of O-GlcN Acylated sites on tau protein is lower than the number of phosphorylation sites. Although the functional significance of O-GlcNAc modification is not fully understood, it is implicated in transcriptional regulation, protein degradation, cell activation, cell cycle regulation and the proper assembly of multimeric protein complexes [32,33]. O-GlcNAcylation may have a role in mediating interaction of tau with tubulin or in subcellular localization and degradation of tau [32,33-35].