title: ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer's disease mouse model.
abstract: The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice.
authors.affiliation: Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117456, Singapore.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Chan
authors.affiliation: Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117456, Singapore.|Memory Networks Program, Neurobiology and Ageing Program, Life Sciences Institute, National University of Singapore 117456, Singapore.
authors.forename: Mahesh Shivarama
authors.initials: MS
authors.lastname: Shetty
authors.affiliation: Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117456, Singapore.|Memory Networks Program, Neurobiology and Ageing Program, Life Sciences Institute, National University of Singapore 117456, Singapore.
authors.forename: Sreedharan
authors.initials: S
authors.lastname: Sajikumar
authors.affiliation: Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.|Memory Ageing and Cognition Centre (MACC), National University Health System (NUHS) 117599, Singapore.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chen
authors.affiliation: Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117456, Singapore.|Memory Networks Program, Neurobiology and Ageing Program, Life Sciences Institute, National University of Singapore 117456, Singapore.
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
authors.affiliation: Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117456, Singapore.
authors.forename: Boon-Seng
authors.initials: BS
authors.lastname: Wong
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D007328:Insulin; D018091:Receptors, AMPA