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Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms

Pathophysiology Department, Key Laboratory of Neurological Disease of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

¹Correspondence: Department of Pathophysiology, Key Laboratory of Neurological Disease of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. E-mail: wangjz{at}mails tjmu.edu.cn

To investigate the upstream effector that led to tau hyperphosphorylation, nitration, and accumulation as seen in Alzheimer’s disease brain, and the underlying mechanisms, we bilaterally injected SIN-1, a recognized peroxynitrite donor, into the hippocampus of rat brain. We observed that the level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h after drug administration, and these alterations were prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. Concomitantly, we detected a significant activation in glycogen synthase kinase-3ß (GSK-3ß) and p38 MAPKs, including p38, p38ß, and p38, but no obvious change was measured in the activity of p38, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, in which the activity of 20S proteasome was significantly arrested in SIN-1-injected rats. Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis. These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3ß, p38, p38ß, p38 isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.—Zhang, Y-J., Xu, Y-F., Liu, Y-H., Yin, J., Li, H-L., Wang, Q., Wang, J-Z. Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.

Key Words: tau • glycogen synthase kinase-3ß • p38 MAPKs • proteasome

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