Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
We recently found that sAPPα decreases amyloid-beta generation by directly associating with β-site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3β)-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPPα also reduces GSK3β-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over-expressing mice. Further, recombinant human sAPPα evoked the same phenomenon in SH-SY5Y cells. Further, in SH-SY5Y cells over-expressing BACE1, and HeLa cells over-expressing human tau, sAPPα reduced GSK3β activity and tau phosphorylation. Importantly, the reductions in GSK3β activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ-secretase inhibition. In accord, AD mice over-expressing human sAPPα had less GSK3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β-processing and GSK3β-mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis.
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.|Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
Juan
J
Deng
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
Ahsan
A
Habib
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
Demian F
DF
Obregon
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Steven W
SW
Barger
Neuroimmunology Laboratory, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
Brian
B
Giunta
Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
Yan-Jiang
YJ
Wang
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
Huayan
H
Hou
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
Darrell
D
Sawmiller
Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
Jun
J
Tan
D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
Alzheimer's disease; BACE1; GSK3β; sAPPα; tau