A PROTEIN-KINASE, PKN, ACCUMULATES IN ALZHEIMER NEUROFIBRILLARY TANGLES AND ASSOCIATED ENDOPLASMIC RETICULUM-DERIVED VESICLES AND PHOSPHORYLATES TAU-PROTEIN

A possible role for a protein kinase, PKN, a fatty acid-activated seri ne/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the p athology of Alzheimer's disease (AD) using a sensitive immunocytochemi stry on postmortem human brain tissues and a kinase assay for human ta u protein. The present study provides evidences by light, electron, an d confocal laser microscopy that in control human brains, PKN is enric hed in neurons, where the kinase is concentrated in a subset of endopl asmic reticulum (ER) and ER-derived vesicles localized to the apical c ompartment of juxtanuclear cytoplasm, as well as late endosomes, multi vesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD- affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs ) and their major constituent, abnormally modified tau. PKN was also f ound in degenerative neurites within senile plaques. In addition, we r eport that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.