1. Secreted amyloid precursor protein alpha activates neuronal insulin receptors and prevents diabetes-induced encephalopathy.
- Author
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Aulston BD, Schapansky J, Huang Y, Odero GL, and Glazner GW
- Subjects
- Amyloid beta-Peptides pharmacology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor pharmacology, Animals, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Glycated Hemoglobin metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Neurons drug effects, Peptide Fragments genetics, Peptide Fragments pharmacology, Phosphorylation physiology, Protein Binding physiology, Signal Transduction drug effects, Signal Transduction genetics, Unfolded Protein Response genetics, tau Proteins metabolism, Amyloid beta-Protein Precursor metabolism, Brain Diseases etiology, Brain Diseases prevention & control, Diabetes Mellitus, Experimental complications, Neurons metabolism, Peptide Fragments metabolism, Receptor, Insulin metabolism
- Abstract
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals. To further examine the effects of sAPPα on the diabetic brain, we next rendered sAPPα overexpressing mice insulin depleted and found that sAPPα blocked aberrant tau phosphorylation (T231) in cortical tissue after 16 weeks diabetes. sAPPα overexpression also prevented hyperphosphorylation of AKT/GSK3 and activation of the unfolded protein response (UPR). In total, these data show sAPPα binds and activates neuronal IRs and that sAPPα has a protective effect on diabetic brain tissue., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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