Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity.
Pathological changes of Alzheimer disease are characterized by cerebral cortical atrophy as a result of degeneration and loss of neurons. Typical histological lesions include numerous senile plaques composed of deposits of amyloid beta-protein and neurofibrillary tangles consisting predominantly of ubiquitin and highly phosphorylated tau proteins. Previously, tau protein kinase I (TPK I) was purified and its cDNA was cloned. To examine the biological role of this enzyme in neurons, we have studied the induction of its kinase activity in primary cultures of embryonic rat hippocampal neurons. Treatment of cultures with amyloid beta-protein significantly increased TPK I activity and induced the appearance of tau proteins recognized by the Alz-50 monoclonal antibody. In addition, though amyloid beta-protein was neurotoxic, either cycloheximide or actinomycin D prevented neuronal death. Death was also prevented by TPK I antisense oligonucleotides but not by sense oligonucleotides. These observations suggest that rat hippocampal neurons undergo programmed cell death in response to amyloid beta-protein and that TPK I is a key enzyme in this process.
Takashima
A
A
Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Noguchi
K
K
Sato
K
K
Hoshino
T
T
Imahori
K
K
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D038362:Glycogen Synthase Kinase 3; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D007700:Kinetics; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase