title: Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer's Disease.
abstract: Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer's disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer's disease.
authors.affiliation: Univ Paris-Saclay, Paris, France.|Univ Paris-Sud, Paris-Saclay Neuroscience Institute (Neuro-PSI), Orsay, France.|CNRS, Orsay, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Guillot
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.affiliation: Univ Paris-Saclay, Paris, France.|Univ Paris-Sud, Paris-Saclay Neuroscience Institute (Neuro-PSI), Orsay, France.|CNRS, Orsay, France.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Levasseur
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi O
authors.initials: PO
authors.lastname: Miettinen
authors.affiliation: Univ Paris-Saclay, Paris, France.|Univ Paris-Sud, Paris-Saclay Neuroscience Institute (Neuro-PSI), Orsay, France.|CNRS, Orsay, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Laroche
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Univ Paris-Saclay, Paris, France.|Univ Paris-Sud, Paris-Saclay Neuroscience Institute (Neuro-PSI), Orsay, France.|CNRS, Orsay, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Davis
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Alzheimer’s disease; Beclin 1; CA1; NFκB; autophagy; cortex; dentate gyrus; inflammation; mTOR; transgenic mice