Increased production of paired helical filament epitopes in a cell culture system reduces the turnover of tau.
To investigate the regulation of posttranslational modifications of tau that might be pertinent to the production of the paired helical filament (PHF) of Alzheimer's disease, we incubated human neuroblastoma cells with the protein phosphatase inhibitor okadaic acid. This treatment results in increased immunoreactivity of tau with the monoclonal antibodies Alz-50, PHF-1, T3P, and NP8, a reduction in Tau-1 immunoreactivity, and an elevation in apparent molecular weight of tau. Moreover, our data demonstrate that accumulation of phosphates in tau leads to a decrease in the turnover rate of tau in the neuroblastoma cells. It is suggested that similar build-up of hyperphosphorylated tau in the neuronal perikarya may represent an early event in PHF formation. The present system facilitates the investigation of regulatory mechanisms governing the occurrence of PHF epitopes, their effects on neuronal cell metabolism, and possible pharmacological intervention.
Vincent
I
I
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461.
Rosado
M
M
Kim
E
E
Davies
P
P
D000469:Alkaline Phosphatase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D008715:Methionine / Q000378:metabolism; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
D000939:Epitopes; D004988:Ethers, Cyclic; D011506:Proteins; D016875:tau Proteins; D019319:Okadaic Acid; D008715:Methionine; D000469:Alkaline Phosphatase; D010749:Phosphoprotein Phosphatases