P2-142: Decreased protein phosphatase 2A in Down syndrome brain: A cause of neurofibrillary degeneration

Abstract

Individuals with Down syndrome (DS) develop neurofibrillary tangles, a characteristic brain lesion of Alzheimer's disease (AD), when they reach the fourth decade of life. Neurofibrillary tangles are composed of highly aggregated and phosphorylated form of microtubule associated protein tau. In AD, hyperphosphorylation of tau partially results from down-regulation of protein phosphatase (PP) 2A, a major brain tau phosphatase. The abnormal hyperphosphorylation of tau in DS had not yet been characterized, and its causes were not understood. The levels and site-specific phosphorylation of tau as well as the levels of several brain PPs in the temporal cortices of 6 DS (58.8 ± 3.8 years old) and 6 controls (68.0 ± 9.5 years old) were determined by using quantitative Western blot analysis. Linear correlation between the levels of PP2A catalytic subunit and the level of tau or tau phosphorylation at individual phosphorylation sites was analyzed by using Microsoft Excel 2003. We found that the level of the catalytic subunit of PP2A, but not of PP1, PP2B or PP5, was dramatically decreased. The decrease of PP2A level correlated negatively to tau level and tau phosphorylation at several abnormal hyperphosphorylation sites, including Ser199, Thr205, Thr212, Ser262, Ser396 and Ser422. These findings indicate that the down-regulation of PP2A might be involved in the abnormal hyperphosphorylation and accumulation of tau and thus neurofibrillary degeneration in DS.