INTRODUCTION

Argyrophilic cytoplasmic neuronal and glial inclusions are characteristic of a number of sporadic neurodegenerative disorders, including Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and argyrophilic grain disease (ADG), that collectively are referred to as tauopathies (Lee et al., 2001). At the electron microscopic level inclusions in the tauopathies are non-membrane-bound filamentous aggregates composed of the microtubule-associated protein tau. The tau in the inclusions is abnormal in a number of respects, not the least of which is its fibrillar state. Tau is normally a soluble protein that is unstructured and resistant to heat and strong acids. It binds to microtubules and promotes polymerization and stabilization of microtubules. The functional attributes of tau are regulated by phosphorylation, with phosphorylated forms of tau having decreased ability to promote microtubule stability (Spillantini & Goedert, 1998; Delacourte & Buee, 1997). Fibrillar tau is abnormally phosphorylated with far more phosphate groups than normal tau. There are approximately 20 phosphorylation sites on tau and multiple kinases that are capable of phosphorylating tau. The degree of phosphorylation of the various sites contributes to great microheterogeneity in tau within the brain (Spillantini & Goedert, 1998).

In human adult brain, alternative mRNA splicing of a single gene on chromosome 17 yields six major tau isoforms (Goedert et al., 1989a, 1995; Delacourte & Buee, 1997). Exons 2, 3 and 10 are alternatively spliced. Alternative splicing of exon 10 gives rise to tau isoforms with three (exon 10-) or four (exon 10+) conserved 30–32 amino acid repeats in the microtubule-binding domain, so-called three repeat tau (3R tau) and four repeat tau (4R tau).