title: Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice.
abstract: Human ApoE4 accelerates memory decline in ageing and in Alzheimer's disease. Although intranasal insulin can improve cognition, this has little effect in ApoE4 subjects. To understand this ApoE genotype-dependent effect, we examined brain insulin signaling in huApoE3 and huApoE4 targeted replacement (TR) mice. At 32 weeks, lower insulin receptor substrate 1 (IRS1) at S636/639 and Akt phosphorylation at T308 were detected in fasting huApoE4 TR mice as compared to fasting huApoE3 TR mice. These changes in fasting huApoE4 TR mice were linked to lower brain glucose content and have no effect on plasma glucose level. However, at 72 weeks of age, these early changes were accompanied by reduction in IRS2 expression, IRS1 phosphorylation at Y608, Akt phosphorylation at S473, and MAPK (p38 and p44/42) activation in the fasting huApoE4 TR mice. The lower brain glucose was significantly associated with higher brain insulin in the aged huApoE4 TR mice. These results show that ApoE4 reduces brain insulin signaling and glucose level leading to higher insulin content.
authors.affiliation: 1] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2].
authors.forename: Qi-Rui
authors.initials: QR
authors.lastname: Ong
authors.affiliation: 1] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2].
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Chan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Lim
authors.affiliation: 1] Departments of Medicine and Neurology, University of California, Los Angeles, USA [2] Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Veterans Affairs Medical Center, North Hills, California, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cole
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Boon-Seng
authors.initials: BS
authors.lastname: Wong
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000172:deficiency / Q000235:genetics*; D001786:Blood Glucose; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D015870:Gene Expression; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D002784:Cholesterol; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose