The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes.

Tau was discovered as a protein that co-purified with brain microtubules, and which promoted tubulin polymerization and stabilization. Its principal location is in the neurons, particularly axons, although there are reports of tau or tau-like proteins in glial cells and in peripheral tissues. In dendrites mitogenactivated protein 2 (MAP2) appears to have a role analogous to that of tau in axons. In this Commentary we discuss the regulation of the phosphorylation state of tau, a process that is important in determining its functional properties and is of relevance in the understanding of mechanisms of neurodevelopment and neurodegeneration. Cloning of bovine and human tau has demonstrated only one tau gene, but several different isoforms can be produced at different stages of development or in different nervous tissues (Fig. 1). The isoforms differ from each other by possession of one or two amino terminal inserts (1N or 2N) of unknown function and three or four domains (3R or 4R) that appear to be the main sites for interaction between tau and tubulin. These microtubule binding domains are homologous with domains, presumably serving a similar purpose, in MAP2c. The expression of the different isoforms is developmentally regulated, and it is hypothesized that both the differential expression of isoforms and the phosphorylation of tau are important mechanisms whereby the functional characteristics of microtubule binding and hence cytoskeletal stability are regulated during neurodevelopment. Thus, in fetal and neonatal human and rat CNS only one form (the smallest), 0N3R, is synthesized, with the larger isoforms appearing between postnatal days 12 and 20 in rat. In the peripheral nervous system a larger isoform, ‘‘big tau’’, with an extra 254–333 amino-acid insert, is found. A further form of bovine tau has been reported with another smaller insert, but this has not been found in any other species. Alzheimer’s disease (AD) is characterized by amyloid-containing neuritic plaques consisting primarily of deposits of amyloid â protein (Aâ), now known to be a peptide of 39–43 amino acids, and neurofibrillary tangles (NFT) whose fibrils consist very largely of tau protein. Plaques are large and extracellular, and appear to develop from diffuse deposits into plaques with a dense core. NFT appear to form intracellularly, and NFT-containing cells lose the rest of their characteristic cytoskeleton. Extracellular or ‘‘ghost’’ NFT are also found, apparently being all that remains after the neurons in which they formed died and were destroyed. Electron microscopy shows that NFT are composed of filaments that appear twisted together in pairs, referred to as paired helical filaments (PHF). The relationship between NFT and plaques has not been determined but the hypothesis that deposition of amyloid triggers a cascade of events leading to the accumulation of PHF in NFT and hence to neuronal death and clinical dementia has been widely accepted. Direct evidence in favour of such a hypothesis is, however, scanty, despite a great deal of research in the area, and it is possible that other sequential relationships between amyloid deposition and PHF formation exist. Tau was shown by Selden and Pollard and by Lindwall and Cole to be a phosphoprotein, and isolated microtubules contained protein kinase activity that phosphorylated tau. However, interest Abbreviations: Aâ, amyloid â; AD, Alzheimer’s disease; APP, amyloid precursor protein; CaMPK II, calcium calmodulin kinase 2; cAMP-PK, cAMP-dependent protein kinase; GSK-3, glycogen synthase kinase-3; MAP2, microtubule-associated protein 2; MAPK, mitogenactivated protein kinase; NFT, neurofibrillary tangle; PHF, paired helical filament; PKA, protein kinase A; PKC, protein kinase C; PP, protein serine/threonine phosphatase; SAPK, stress-activated protein kinase; TPK-I and -II, tau protein kinases-I and -II; TTK, tau-tubulin kinase. Pergamon Neuroscience Vol. 78, No. 2, pp. 309–324, 1997 Copyright ? 1997 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306–4522/97 $17.00+0.00 PII: S0306-4522(96)00577-5