Subcellular distribution of protein phosphatases and abnormally phosphorylated τ in the temporal cortex from Alzheimer's disease and control brains

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease (AD). In vitro studies have shown that protein phosphatases PP-2A and PP-2B can convert Alzheimer like tau to its normal state and that the activities of PP-1, PP-2A, and phosphotyrosyl-protein phosphatase (PTP) are reduced in AD brain. However, to have a direct effect on the regulation of phosphorylation on tau, these enzymes have to exist in neurons. Using specific polyclonal antibodies the levels of protein phosphatases PP-1, PP-2A, and PP-2B were determined by indirect ELISA in superior temporal cortical gray matter of AD and control brains. The protein levels of PP-2A and PP-2B were significantly increased in postsynaptosomal supernatant 2 (S2) of the AD group, and this alteration showed a significant linear correlation with levels of hyperphosphorylated tau. PP-1 and PTP-1B levels were not significantly changed in any of the AD fractions. Because of the large variation from case to case, the activity levels of none of the phosphatases investigated were significantly different between the AD and control groups. However, the PP-2B specific activity (activity/protein) showed a significant linear inverse correlation with hyperphosphorylated tau. These studies suggest that any attempt by the AD brain to compensate for the decreased tau phosphatase activity remains unsuccessful and that the decrease in phosphatase activity might contribute to increased levels of abnormally phosphorylated tau.