Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment.
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.
Kim
D
D
Department of Psychobiology, University of California, Irvine 92697-4540, USA. dhkim@www.amc.seoul.kr
Su
J
J
Cotman
C W
CW
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*
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D019319:Okadaic Acid; D007770:L-Lactate Dehydrogenase