Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation.
Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan.
Takeshi
T
Kanno
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan.
Ayako
A
Tsuchiya
Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, 650-8530, Japan.
Akito
A
Tanaka
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan. tnishizaki@bioresorganization.com.
Tomoyuki
T
Nishizaki
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D051744:Protein Kinase C-epsilon; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
Akt; Alzheimer’s disease; GSK-3β; PKCε; Protein tyrosine phosphatase 1B; Tau