Alzheimer’s disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mech- anismisnotclear.Weanalyzedtheeffectofinsulinonseveralmolecularstepsofamyloidprecursor protein (APP) processing and-amyloid (A) intracellular accumulation in a panel of human neu- ronalcellsandinhumanembryonickidney293cellsoverexpressingAPP-695.Thedataindicatethat insulin, via its own receptor and the phosphatidylinositol-3-kinase/AKT pathway, influences APP phosphorylation at different sites. This rapid-onset, dose-dependent effect lasts many hours and mainly concerns dephosphorylation at the APP-T668 site. This effect of insulin was confirmed also in a human cortical neuronal cell line and in rat primary neurons. Cell fractionation and immu- nofluorescence studies indicated that insulin-induced APP-T668 dephosphorylation prevents the translocation of the APP intracellular domain fragment into the nucleus. As a consequence, insulin increases the transcription of antiamyloidogenic proteins such as the insulin-degrading enzyme, involved in A degradation, and-secretase. In contrast, the transcripts of pro-amyloidogenic proteins such as APP, -secretase, and glycogen synthase kinase (Gsk)-3 are de- creased. Moreover, cell exposure to insulin favors the nonamyloidogenic, -secretase-depen- dent APP-processing pathway and reduces A 40 and A 42 intracellular accumulation, promoting their release in the extracellular compartment. The latter effects of insulin are independent of both Gsk-3 phosphorylation and APP-T668 dephosphorylation, as indicated byexperimentswithGsk-3 inhibitorsandwithcellstransfectedwiththenonphosphorylatable mutated APP-T668A analog. In human neuronal cells, therefore, insulin may prevent A for- mation and accumulation by multiple mechanisms, both Gsk-3 dependent and independent

Insulin has multiple antiamyloidogenic effects on human neuronal cells

COPANI, Agata Graziella;SQUATRITO, Sebastiano;
2013-01-01

Abstract

Alzheimer’s disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mech- anismisnotclear.Weanalyzedtheeffectofinsulinonseveralmolecularstepsofamyloidprecursor protein (APP) processing and-amyloid (A) intracellular accumulation in a panel of human neu- ronalcellsandinhumanembryonickidney293cellsoverexpressingAPP-695.Thedataindicatethat insulin, via its own receptor and the phosphatidylinositol-3-kinase/AKT pathway, influences APP phosphorylation at different sites. This rapid-onset, dose-dependent effect lasts many hours and mainly concerns dephosphorylation at the APP-T668 site. This effect of insulin was confirmed also in a human cortical neuronal cell line and in rat primary neurons. Cell fractionation and immu- nofluorescence studies indicated that insulin-induced APP-T668 dephosphorylation prevents the translocation of the APP intracellular domain fragment into the nucleus. As a consequence, insulin increases the transcription of antiamyloidogenic proteins such as the insulin-degrading enzyme, involved in A degradation, and-secretase. In contrast, the transcripts of pro-amyloidogenic proteins such as APP, -secretase, and glycogen synthase kinase (Gsk)-3 are de- creased. Moreover, cell exposure to insulin favors the nonamyloidogenic, -secretase-depen- dent APP-processing pathway and reduces A 40 and A 42 intracellular accumulation, promoting their release in the extracellular compartment. The latter effects of insulin are independent of both Gsk-3 phosphorylation and APP-T668 dephosphorylation, as indicated byexperimentswithGsk-3 inhibitorsandwithcellstransfectedwiththenonphosphorylatable mutated APP-T668A analog. In human neuronal cells, therefore, insulin may prevent A for- mation and accumulation by multiple mechanisms, both Gsk-3 dependent and independent
2013
amyloid beta protein; human cell; neurons
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/14395
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