Activation of mitogen-activated protein kinase cascade and phosphorylationof cytoskeletal proteins after neurone-specific activation of p21ras. II. Cytoskeletal proteins and dendritic morphology

In the present study, we analysed changes in the expression, subcellular di stribution and phosphorylation state of the micro tubule-associated protein tau and other cytoskeletal proteins after neurone-specific activation of t he mitogen-activated protein kinase (MAPK) in the CNS in vivo. We used tran sgenic mice with a neurone-specific expression of activated ras protein (p2 1H-ras(Va112), synapsin I promoter) that is associated with an augmented ac tivity of the MAPK. Chronic activation of MAPK cascade influenced tau prote in phosphorylation, localisation and dendritic morphology. While the amount of tau protein was elevated by 9%, phospho-epitopes detected by the monocl onal antibodies AT270, 12E8 and SM134 were increased by about 21%, 40% and 59% respectively. Steady-state levels of tau mRNA were not affected. Thus, the increase in tau protein was most likely due to stabilisation of tau pro tein by augmented phosphorylation, While in wild-type animals tau protein w as preferentially localised in axons, a prominent immunoreactivity was foun d in the somatodendritic compartment of transgenic mice. This subcellular t ranslocation typically seen in pyramidal neurones was associated with an in crease in the dendritic, calibre by about 30% and is paralleled by an incre ase in tubulin of 19%. We were unable to obtain any morphological indicatio n of neuro degenerative processes in these animals. We suggest that the moderate increase in tau protein and phosphorylation ma y be part of the neuroprotective mechanism. However, further studies on age d transgenic mice will be necessary to establish potential effects on neuro nal viability. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.