Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep26119
Title: ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing A beta impairment of insulin signaling in an Alzheimer's disease mouse model
Authors: Chan, Elizabeth S 
Shetty, Mahesh Shivarama 
Sajikumar, Sreedharan 
Chen, Christopher 
Soong, Tuck Wah 
Wong, Boon-Seng 
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
AMYLOID PRECURSOR PROTEIN
HUMAN APOLIPOPROTEIN-E
PHOSPHODIESTERASE INHIBITOR ROLIPRAM
RECEPTOR SUBUNIT GLUR1
LONG-TERM POTENTIATION
SYNAPTIC PLASTICITY
AMPA RECEPTORS
TARGETED REPLACEMENT
BRAIN INSULIN
WATER MAZE
Issue Date: 18-May-2016
Publisher: NATURE PUBLISHING GROUP
Citation: Chan, Elizabeth S, Shetty, Mahesh Shivarama, Sajikumar, Sreedharan, Chen, Christopher, Soong, Tuck Wah, Wong, Boon-Seng (2016-05-18). ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing A beta impairment of insulin signaling in an Alzheimer's disease mouse model. SCIENTIFIC REPORTS 6 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/srep26119
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.
Source Title: SCIENTIFIC REPORTS
URI: https://scholarbank.nus.edu.sg/handle/10635/218889
ISSN: 20452322
DOI: 10.1038/srep26119
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