Back to Search
Start Over
Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
- Source :
-
Journal of neurochemistry [J Neurochem] 2015 Nov; Vol. 135 (3), pp. 630-7. Date of Electronic Publication: 2015 Sep 24. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (© 2015 International Society for Neurochemistry.)
- Subjects :
- Animals
Cell Line, Tumor
Cells, Cultured
Dose-Response Relationship, Drug
Glycogen Synthase Kinase 3 beta
Humans
Mice
Mice, Inbred C57BL
Phosphorylation drug effects
Phosphorylation physiology
Signal Transduction drug effects
Amyloid beta-Protein Precursor pharmacology
Glycogen Synthase Kinase 3 physiology
Signal Transduction physiology
tau Proteins antagonists & inhibitors
tau Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 135
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26342176
- Full Text :
- https://doi.org/10.1111/jnc.13351