Phospholipid transfer protein reduces phosphorylation of tau in human neuronal cells.
Tau function is regulated by phosphorylation, and abnormal tau phosphorylation in neurons is one of the key processes associated with development of Alzheimer's disease and other tauopathies. In this study we provide evidence that phospholipid transfer protein (PLTP), one of the main lipid transfer proteins in the brain, significantly reduces levels of phosphorylated tau and increases levels of the inactive form of glycogen synthase kinase-3beta (GSK3 beta) in HCN2 cells. Furthermore, inhibition of phosphatidylinositol-3 kinase (PI3K) reversed the PLTP-induced increase in levels of GSK3 beta phosphorylated at serine 9 (pGSK3 beta(Ser9)) and partially reversed the PLTP-induced reduction in tau phosphorylation. We provide evidence that the PLTP-induced changes are not due to activation of Disabled-1 (Dab1), insofar as PLTP reduced levels of total and phosphorylated Dab1 in HCN2 cells. We have also shown that inhibition of tyrosine kinase activity of insulin receptor (IR) and/or insulin-like growth factor 1 (IGF1) receptor (IGFR) reverses the PLTP-induced increase in levels of phosphorylated Akt (pAkt(Thr308) and pAkt(Ser473)), suggesting that PLTP-mediated activation of the PI3K/Akt pathway is dependent on IR/IGFR receptor tyrosine kinase activity. Our study suggests that PLTP may be an important modulator of signal transduction pathways in human neurons.
Dong
Weijiang
W
Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington School of Medicine, Seattle, Washington 98109, USA.
Albers
John J
JJ
Vuletic
Simona
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D016875:tau Proteins; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3