The intracellular accumulation of tau protein and its aggregation into filamentous deposits is the intracellular hallmark of neurofibrillary degenerative diseases such as Alzheimer’s Disease and familial tauopathies in which tau

The intracellular accumulation and aggregation of abnormal filaments composed primarily of the microtubule associated protein tau (paired helical filaments (PHFs) and straight filaments (SFs)) has long been known as a hallmark of a variety of neurodegenerative conditions, including Alzheimer’s Disease (AD), Pick’s Disease, Progressive Supernuclear Palsy, and Corticobasal Degeneration (Muruyama et al., 1990; Perry et al., 1987; Probst et al., 1988; Dickson et al., 1996; reviewed by Spillantini and Goedert, 1998). These filaments eventually form large aggregations (neurofibrillary tangles (NFTs)) that can fill the somata of affected neurons, displacing normal cytoskeletal elements such as microtubules (MTs) and neurofilaments (NFs) (McKee et al., 1989; Bancher et al., 1989; Perry et al., 1991). This process (neurofibrillary degeneration) is accompanied by the development of other characteristic abnormalities, notably tau hyperphosphorylation, loss of protein phosphatase 2A activity (Gong et al., 1995), lysosomal hypertrophy (Nixon et al., 1992), loss of synapses, the beading and degeneration of distal dendrites (McKee et al., 1989; Braak et al., 1994; Braak and Braak, 1998; Praprotnik et al., 1996a; Velasco et al., 1998) and axonal degeneration (Kowall and Kosik, 1987). NFT formation is also well correlated spatiotemporally with the pattern of neuronal death and the loss of mental abilities in patients with AD (Arriagada et al., 1991; McKee et al., 1991; Bobinski et al., 1997; Gomez-Isla et al., 1998). However, despite this prominence in the pathology of neurodegenerative disease, tau filament formation and the cytoskeletal neurofibrillary changes associated with it have until recently been widely thought to be secondary to other pathogenetic factors, particularly in AD. This has been due mainly to the lack of known disease associated mutations in the tau coding sequence that might provide a causal link between tau and a plausible pathogenetic mechanism for any major neurodegenerative disease. Recently, linkage studies of familial forms of several non-AD neurofibrillary degenerative conditions (Clark et al., 1998; Reed et al., 1998; Hutton et al., 1998; Hong et al., 1998) have shown that mutations within the coding sequence of human tau (htau) are linked with a significant proportion of familial neurodegenerative disease cases; these are now frequently referred to collectively as ‘tauopathies’. Such findings have resulted in a renewed interest in understanding the cellular mechanisms underlying tau filament formation in vivo. In particular, the demonstration that mutations causing abnormalities in tau splicing and primary structure can cause neurofibrillary degeneration (Hutton et al., 1998; Hong et al., 1998), and also affect both tau filament formation in vitro (Nacharaju et al., 1999; Goedert et al., 1999), and the binding 1373 Journal of Cell Science 113, 1373-1387 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS1240