title: Altered cerebral insulin response in transgenic mice expressing the epsilon-4 allele of the human apolipoprotein E gene.
abstract: Apolipoprotein E epsilon-4 (APOEε4 or APOE4), an allelic variation of the APOE gene, not only increases the risk of developing the late-onset form of Alzheimer's disease (AD), but also influences the outcome of treatment. Indeed, data from clinical studies show that the beneficial effect of insulin on cognition is blunted in APOE4 carriers. To investigate how APOE impacts insulin response, we assessed the effects of an acute insulin injection in APOE3- and APOE4-targeted replacement mice that respectively express the human APOE3 or APOE4 isoform instead of the endogenous murine ApoE protein. We evaluated cognition, insulin signaling and proteins implicated in Aβ transport and tau phosphorylation in the cortex and brain capillaries. We found that a single acute insulin injection increased Akt pSer473 in APOE4 compared to APOE3 mice (+113% versus +78.5%), indicating that APOE4 carriage potentiates activation of insulin upstream signaling pathway in the brain. Insulin also led to decreased concentrations of the receptor for advanced glycation endproducts (RAGE) in brain capillaries in both groups of mice. Moreover, higher phosphorylation of tau at Ser202, one of the key markers of AD neuropathology, was observed in insulin-injected APOE4 mice (+44%), consistent with findings in human APOE4 carriers (+400% compared to non-carriers). Therefore, our data suggest that APOE4 carriage leads to an increased insulin-induced activation of cerebral Akt pathway, associated with higher AD-like tau neuropathology. Our results provide evidence of altered insulin signaling in APOE4 carriers as well as a possible mechanism to explain the absence of cognitive benefit from insulin therapy in these individuals.
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, QC, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Traversy
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, QC, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada.
authors.forename: Milène
authors.initials: M
authors.lastname: Vandal
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada.
authors.forename: Cyntia
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, QC, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada.
authors.forename: Marine
authors.initials: M
authors.lastname: Tournissac
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, QC, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada.
authors.forename: Ariane
authors.initials: A
authors.lastname: Giguère-Rancourt
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: A David
authors.initials: AD
authors.lastname: Bennett
authors.affiliation: Faculté de pharmacie, Université Laval, Québec, QC, Canada; Axe Neurosciences, Centre de recherche du CHU-Q (Pavillon CHUL), Québec, QC, Canada; Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada. Electronic address: frederic.calon@pha.ulaval.ca.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D007004:Hypoglycemic Agents; D007328:Insulin; D000067759:Receptor for Advanced Glycation End Products; D016875:tau Proteins; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: APOE4; Alzheimer’s disease; Insulin