Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A.
Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease, and is the major protein subunit of paired helical filaments. There is also a significant pool of non-paired helical filament abnormally phosphorylated tau in Alzheimer's disease brain. In the present study, the site-specific dephosphorylation of this Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A was studied and compared with that by protein phosphatase-2B. The dephosphorylation was detected by its interaction with several phosphorylation-dependent antibodies to various abnormal phosphorylation sites. Protein phosphatase-2A was able to dephosphorylate the abnormally phosphorylated tau at Ser-46, Ser-199, Ser-202, Ser-396 and Ser-404, but not at Ser-235 (the amino acids are numbered according to the largest isoform of human tau, tau441). Two major types of protein phosphatase-2A, protein phosphatase-2A1 and -2A2, dephosphorylated the abnormally phosphorylated tau at approximately the same rate. After the abnormally phosphorylated tau was dephosphorylated by protein phosphatase-2A, its relative mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increased. The dephosphorylation of the abnormal tau by protein phosphatase-2A1 and -2A2 was markedly stimulated by Mn2+. These results suggest that tau dephosphorylation is catalysed by protein phosphatase-2A in addition to protein phosphatase-2B. A deficiency of either protein phosphatase-2A or -2B, or both, may be involved in abnormal phosphorylation of tau in Alzheimer's disease.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
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D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011107:Polylysine / Q000494:pharmacology; D054648:Protein Phosphatase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*
D016875:tau Proteins; D011107:Polylysine; D008345:Manganese; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D008274:Magnesium