Rosiglitazone reduces tau phosphorylation via JNK inhibition in the hippocampus of rats with type 2 diabetes and tau transfected SH-SY5Y cells.
Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. Rosiglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist, which is an anti-diabetic agent against type 2 diabetes, is currently in Phase III clinical trials in AD patients because rosiglitazone reduces β-amyloid (Aβ) pathology and inflammation. However, few studies have investigated whether rosiglitazone affects tau phosphorylation, another critical pathological feature of AD. Thus, we investigated it using OLETF type 2 diabetic rats and streptozotocin-injected type 1 diabetic mice. Interestingly, rosiglitazone reduced tau phosphorylation only in the hippocampus of OLETF type 2 diabetes rats, and not in that of STZ-injected type 1 diabetes mice. The activity of JNK was reduced in the hippocampus of rosiglitazone-treated OLETF rats, correlating with a reduction in tau phosphorylation, however, which was not correlated with GSK3β activity. In human tau-transfected SH-SY5Y neuronal cell line, reduction of tau phosphorylation was also associated with reduction of JNK activity, not of GSK3β activity. Hence, rosiglitazone could be used in reducing tau phosphorylation through JNK inactivation for therapeutic effects in type 2 diabetes related Alzheimer's disease.
Yoon
Seung-Yong
SY
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea.
Park
Jeong-Su
JS
Choi
Jung-Eun
JE
Choi
Jin-Myung
JM
Lee
Woo-Je
WJ
Kim
Seong-Who
SW
Kim
Dong-Hou
DH
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007223:Infant; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D020334:Rats, Inbred OLETF; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D016875:tau Proteins / Q000378:metabolism*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D016875:tau Proteins; D000077154:Rosiglitazone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3