TY - JOUR
T1 - Physiological regulation of tau phosphorylation during hibernation
AU - Su, Bo
AU - Wang, Xinglong
AU - Drew, Kelly L.
AU - Perry, George
AU - Smith, Mark A.
AU - Zhu, Xiongwei
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2008/6
Y1 - 2008/6
N2 - The microtubule-associated protein tau is abnormally hyperphosphorylated in the brains of individuals with Alzheimer disease and other tauopathies, and is believed to play a critical role in the pathogenesis of these diseases. While the mechanisms leading to abnormal tau phosphorylation remain elusive, the recent demonstration of reversible tau phosphorylation during hibernation provides an ideal physiological model to study this critical process in vivo. In this study, arctic ground squirrels (AGS) during hibernation were used to study mechanisms related to tau hyperphosphorylation. Our data demonstrate that tau is hyperphosphorylated at all six sites (S199, T205, S214, S262, S396, and S404) examined in hibernating AGS. Interestingly, only three of these sites (S199, S262, and S404) are dephosphorylated in aroused animals, suggesting a reversible phosphorylation at selective sites. Summer-active AGS demonstrated the lowest tau phosphorylation at all these sites. To explore the mechanisms underlying increased tau phosphorylation during hibernation, the expression level and enzyme activity of various potential tau kinases and protein phosphatases were examined. The kinetic analysis of enzyme activity at different temperatures revealed differential changes in enzyme activity with temperature decline. Specifically, increased protein kinase A activity, decreased protein phosphatase 2A activity, as well as substantial contribution from glycogen synthase kinase-3β, likely play a key role in increased tau phosphorylation during hibernation in AGS.
AB - The microtubule-associated protein tau is abnormally hyperphosphorylated in the brains of individuals with Alzheimer disease and other tauopathies, and is believed to play a critical role in the pathogenesis of these diseases. While the mechanisms leading to abnormal tau phosphorylation remain elusive, the recent demonstration of reversible tau phosphorylation during hibernation provides an ideal physiological model to study this critical process in vivo. In this study, arctic ground squirrels (AGS) during hibernation were used to study mechanisms related to tau hyperphosphorylation. Our data demonstrate that tau is hyperphosphorylated at all six sites (S199, T205, S214, S262, S396, and S404) examined in hibernating AGS. Interestingly, only three of these sites (S199, S262, and S404) are dephosphorylated in aroused animals, suggesting a reversible phosphorylation at selective sites. Summer-active AGS demonstrated the lowest tau phosphorylation at all these sites. To explore the mechanisms underlying increased tau phosphorylation during hibernation, the expression level and enzyme activity of various potential tau kinases and protein phosphatases were examined. The kinetic analysis of enzyme activity at different temperatures revealed differential changes in enzyme activity with temperature decline. Specifically, increased protein kinase A activity, decreased protein phosphatase 2A activity, as well as substantial contribution from glycogen synthase kinase-3β, likely play a key role in increased tau phosphorylation during hibernation in AGS.
KW - Hibernation
KW - Protein kinase A
KW - Protein phosphatase 2A
KW - Reversible phosphorylation
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=44649165063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44649165063&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2008.05294.x
DO - 10.1111/j.1471-4159.2008.05294.x
M3 - Article
C2 - 18284615
AN - SCOPUS:44649165063
VL - 105
SP - 2098
EP - 2108
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -