Proteasome inhibition increases tau accumulation independent of phosphorylation.
An intrinsic link between proteasome and tau degradation in Alzheimer's disease (AD) has been suggested, however, the role of proteasome in the proteolysis of tau is still uncertain. Here, we investigated the influence of proteasome inhibition on the accumulation, phosphorylation, ubiquitination, solubility of tau and the memory retention in rats. We observed that lactacystin inhibited the proteasome activities and increased the level and insolubility of different tau species, including phosphorylated tau. The elevation of the phosphorylated tau was no longer present and the level of pS214 and pT231 tau was even lower than normal level after normalized to total tau. Inhibition of proteasome resulted in activation of cAMP-dependent protein kinase, glycogen synthase kinases-3beta and cyclin-dependent kinase-5, and inhibition of protein phosphatase-2A and c-Jun N-terminal kinase (JNK). Proteasome inhibition did not affect the memory retention of the rats. We conclude that proteasome inhibition increases accumulation and insolubility of tau proteins independent of tau phosphorylation, and JNK inhibition may be partially responsible for the relatively decreased phosphorylation of tau in the rat brains.
Liu
Ying-Hua
YH
Department of Pathophysiology, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Wei
Wei
W
Yin
Jun
J
Liu
Gong-Ping
GP
Wang
Qun
Q
Cao
Fu-Yuan
FY
Wang
Jian-Zhi
JZ
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; C489131:Mapt protein, rat; D061988:Proteasome Inhibitors; D016875:tau Proteins; C067713:lactacystin; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; C495907:Cdk5 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine