PHOSPHOPROTEIN PHOSPHATASE-ACTIVITIES IN ALZHEIMER-DISEASE BRAIN

Microtubule-associated protein tau is known to be hyperphosphorylated in Alzheimer disease brain and this abnormal hyperphosphorylation is a ssociated with an inability of tau to promote the assembly of microtub ule in the affected neurons. Our previous studies demonstrated that ab normally phosphorylated tau could be dephosphorylated after treatment with alkaline phosphatase, thereby suggesting that the abnormal phosph orylation of tau might in part be the result of a deficiency of the ph osphoprotein phosphatase system in patients with Alzheimer disease. In the present study we used P-32-labeled phosphorylase kinase and poly( Glu,Tyr) 4:1 as substrates to measure phosphoprotein phosphatase activ ities in Alzheimer disease and control brains. The activities of phosp hoseryl/phosphothreonyl-protein phosphatase types 1, 2A, 2B, and 2C an d of phosphotyrosyl-protein phosphatase in frontal gray and white matt ers from 13 Alzheimer brains were determined and compared with those f rom 12 age-matched control brains. The activities of type 1 phosphatas e and phosphotyrosyl phosphatase in gray matter and of type 2A phospha tase in both gray and white matters were significantly lower in Alzhei mer disease brains than in controls. These findings suggest that the h yperphosphorylation of tau in Alzheimer disease brain could result fro m a protein dephosphorylation defect in vivo. The decrease in the phos phatase activities in Alzheimer disease might also be involved in the formation of beta-amyloid by augmenting the amyloidogenic pathway proc essing of beta-amyloid precursor protein.