Altered cerebral insulin response in transgenic mice expressing the epsilon-4 allele of the human apolipoprotein E gene
| Autor: | Milène Vandal, A. David Bennett, Ariane Giguère-Rancourt, Frédéric Calon, Cyntia Tremblay, Marine Tournissac, Marie-Thérèse Traversy |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Genetically modified mouse medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Apolipoprotein E4 Receptor for Advanced Glycation End Products Apolipoprotein E3 Mice Transgenic tau Proteins Article 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Internal medicine mental disorders medicine Animals Humans Hypoglycemic Agents Insulin Phosphorylation Receptor Protein kinase B Biological Psychiatry PI3K/AKT/mTOR pathway Cerebral Cortex biology Endocrine and Autonomic Systems Receptor Insulin Psychiatry and Mental health Insulin receptor 030104 developmental biology biology.protein lipids (amino acids peptides and proteins) Signal transduction human activities Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
| Zdroj: | Psychoneuroendocrinology |
| Popis: | Apolipoprotein E epsilon-4 ( APOEe4 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. |
| Databáze: | OpenAIRE |
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