Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.
Virtually all 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. In AD, neurofibrillary tangles are thought to result from abnormal hyperphosphorylation of tau protein, which, in turn, can result 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. In this study, by using quantitative Western blot analysis, 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. Our results indicate that PP2A is down-regulated in DS brain and suggest that this down-regulation might be involved in the abnormal hyperphosphorylation and accumulation of tau.
Liang
Zhihou
Z
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314-6399, USA.
Liu
Fei
F
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
Wegiel
Jerzy
J
Gong
Cheng-Xin
CX
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013702:Temporal Lobe / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins; D054648:Protein Phosphatase 2