title: Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment.
abstract: Within neurofibrillary tangles and dystrophic neurites of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In the present study, we examined the effect of okadaic acid (OA), a protein phosphatase inhibitor, in rat cultured neurons. Low concentrations of OA induce degeneration of neurites, rounding of cell bodies, detachment from the substratum, and eventual neuronal death. During OA-induced degeneration, SMI-31 immunoreactivity became punctate in neurites at 6 h after OA treatment, and over time, accumulated in cell bodies and dystrophic neurites. Hyperphosphorylation of tau and marked loss of MAP-2-positive dendrites occurred after 6 h of treatment with OA. Thereafter, AT-8 and PHF-1 immunoreactivity accumulated in cell bodies and subsequently appeared in distal axon-like neurites. These results demonstrate that OA treatment induced hyperphosphorylation of tau and preferential dendritic damage, with subsequent accumulation of phosphorylated tau in cell bodies and dystrophic axon-like neurites. OA-induced neurodegeneration may provide a useful model to study AD.
authors.affiliation: Department of Psychobiology, University of California, Irvine 92697-4540, USA. dhkim@www.amc.seoul.kr
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Su
authors.forename: C W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001369:Axons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005333:Fetus / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000648:ultrastructure; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D019319:Okadaic Acid; D007770:L-Lactate Dehydrogenase