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The Journal of Neuroscience, September 15, 1998, 18(18):7402-7410

A Protein Kinase, PKN, Accumulates in Alzheimer Neurofibrillary Tangles and Associated Endoplasmic Reticulum-Derived Vesicles and Phosphorylates Tau Protein

Toshio Kawamata¹, Taizo Taniguchi¹, Hideyuki Mukai², Michinori Kitagawa², Takeshi Hashimoto¹, Kiyoshi Maeda¹, Yoshitaka Ono², and Chikako Tanaka¹

¹ Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji 670, Japan, and ² Department of Biology, Faculty of Science, Kobe University, Nada-ku, Kobe 657, Japan

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular 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 found in degenerative neurites within senile plaques. In addition, we report 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.

Key words: PKN; PRK1; kinase; phosphorylation; endoplasmic reticulum; neurofibrillary tangles; paired helical filaments; tau protein; Alzheimer's disease; immunocytochemistry; kinase assay; human brain; neuron

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187402-09$05.00/0

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