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ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing A? 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 A? 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 A? 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 A?42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and A?42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances A? inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice.

SUBMITTER: Chan ES

PROVIDER: S-EPMC4870502 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer's disease mouse model.

Chan Elizabeth S ES Shetty Mahesh Shivarama MS Sajikumar Sreedharan S Chen Christopher C Soong Tuck Wah TW Wong Boon-Seng BS

Scientific reports 20160518

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 wer ...[more]

PMID: 27189808

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Project description:BackgroundAlzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age-associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy-induced acceleration of AD.MethodsPre-symptomatic young 5XFAD or non-transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14 days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Protein expressions in the CM were analysed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real-time reverse transcription polymerase chain reaction and histological analysis confirmed the expression.ResultsCasting for 2 weeks reduced skeletal muscle weight. Object recognition memory in the cast-attached 5XFAD mice (n = 7, training vs. test, P = 0.3390) was impaired than that in age-matched wildtype (n = 7, training vs. test, P = 0.0523) and non-cast 5XFAD mice (n = 7, training vs. test, P = 0.0473). On 2D-PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast-attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (n = 3, P = 0.0064), plasma (n = 3, P = 0.0386), and hippocampus (n = 3, P = 0.0164) were increased in cast-attached 5XFAD mice than those in non-cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice (n = 4, training vs. test, P = 0.6764). Lipocalin-2 (Lcn2) messenger RNA (mRNA), neuroinflammation-associated factor, was increased in the hippocampus in hemopexin-infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. Lcn2 mRNA levels in the hippocampus were also increased by cast-immobilization of the hindlimbs (n = 6, P = 0.0043).ConclusionsThese findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

Dataset Information

ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing A? impairment of insulin signaling in an Alzheimer's disease mouse model.

Publications

ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer's disease mouse model.

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