title: Attenuation of okadaic acid-induced hyperphosphorylation of cytoskeletal proteins by heat preconditioning and its possible underlying mechanisms.
abstract: An imbalanced phosphorylation system is recognized to be one of the main reasons for Alzheimer-like hyperphosphorylation of cytoskeletal proteins. However, little is known about the strategies rectifying the lesions caused by this disrupted phosphorylation. To search for the means to arrest Alzheimer-like damages and explore the underlying mechanisms, in this study we treated N2a/peuht40 cells with okadaic acid (OA), a specific inhibitor of protein phosphatase-2A (PP-2A) and PP-1, to mimic an Alzheimer-like phosphatase-deficient system and then used heat preconditioning (42 degrees C for 1 hour) to induce the expression of inducible heat shock protein 70 (Hsp70) in the cells. We observed that heat preconditioning arrested OA-induced hyperphosphorylation of neurofilament (NF) protein at SMI34 and SMI33 epitopes as well as hyperphosphorylation of tau at Tau-1 and PHF-1 epitopes. It counteracted OA-induced decrease in PP-2A activity with a concurrent inhibition in constitutive activity of mitogen-activated protein kinases (MAPKs) and cyclic adenosine 5'-monophosphate-dependent protein kinase A (PKA). Conversely, quercetin, a recognized blocker of stress-responsive Hsp70 expression, diminished the effects caused by heat preconditioning. These results suggested that Hsp70 antagonized OA-induced Alzheimer-like NF and tau hyperphosphorylation, and the restoration of PP-2A and inhibition of MAPKs-PKA activity might be part of the underlying mechanisms for the rectification of OA-induced hyperphosphorylation.
authors.affiliation: Pathophysiology Department, Neuroscience Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Ya Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Yong Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Ai Hong
authors.initials: AH
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D011794:Quercetin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D016900:Neurofilament Proteins; C085349:PHF-1 monoclonal antibody; D016875:tau Proteins; D019319:Okadaic Acid; D011794:Quercetin; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2