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Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice.

Chan ES, Chen C, Cole GM, Wong BS - Sci Rep (2015)

Bottom Line: Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration.However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons.Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

View Article: PubMed Central - PubMed

Affiliation: Departments of Physiology Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer's disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein (APP) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among APP, ApoE3xAPP and ApoE4xAPP mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in APP and ApoE4xAPP mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

No MeSH data available.


Related in: MedlinePlus

Aβ42/40 ratio in the ageing ApoExAPP mice.Aβ42/40 ratio in the brain of 26 and 78 weeks old APP (dark grey), ApoE3xAPP (E3XAPP, white) and ApoE4xAPP (E4XAPP, grey) mice. Higher Aβ42/40 ratio was detected in the brain of 78 weeks ApoE4xAPP mice as compared to age-matched ApoE3xAPP and APP mice. Each value represents the mean ± SEM for individual mouse brain sample (26 weeks n = 5, 78 weeks n = 7). One-way ANOVA revealed differences between groups (**p < 0.01).
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f1: Aβ42/40 ratio in the ageing ApoExAPP mice.Aβ42/40 ratio in the brain of 26 and 78 weeks old APP (dark grey), ApoE3xAPP (E3XAPP, white) and ApoE4xAPP (E4XAPP, grey) mice. Higher Aβ42/40 ratio was detected in the brain of 78 weeks ApoE4xAPP mice as compared to age-matched ApoE3xAPP and APP mice. Each value represents the mean ± SEM for individual mouse brain sample (26 weeks n = 5, 78 weeks n = 7). One-way ANOVA revealed differences between groups (**p < 0.01).

Mentions: Aβ42 is the predominant species of Aβ in the AD brain and this peptide concentration will increase more than other Aβ species as AD progresses353637. At 26 weeks, there was no significant difference in the Aβ42/Aβ40 ratio (Fig. 1) between APP, ApoE3xAPP and ApoE4xAPP mice. However, at 78 weeks, post-hoc analysis Tukey-Kramer analysis showed that ApoE4xAPP mice had significantly higher Aβ42/ Aβ40 ratio than APP and ApoE3xAPP mice (Fig. 1).


Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice.

Chan ES, Chen C, Cole GM, Wong BS - Sci Rep (2015)

Aβ42/40 ratio in the ageing ApoExAPP mice.Aβ42/40 ratio in the brain of 26 and 78 weeks old APP (dark grey), ApoE3xAPP (E3XAPP, white) and ApoE4xAPP (E4XAPP, grey) mice. Higher Aβ42/40 ratio was detected in the brain of 78 weeks ApoE4xAPP mice as compared to age-matched ApoE3xAPP and APP mice. Each value represents the mean ± SEM for individual mouse brain sample (26 weeks n = 5, 78 weeks n = 7). One-way ANOVA revealed differences between groups (**p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561911&req=5

f1: Aβ42/40 ratio in the ageing ApoExAPP mice.Aβ42/40 ratio in the brain of 26 and 78 weeks old APP (dark grey), ApoE3xAPP (E3XAPP, white) and ApoE4xAPP (E4XAPP, grey) mice. Higher Aβ42/40 ratio was detected in the brain of 78 weeks ApoE4xAPP mice as compared to age-matched ApoE3xAPP and APP mice. Each value represents the mean ± SEM for individual mouse brain sample (26 weeks n = 5, 78 weeks n = 7). One-way ANOVA revealed differences between groups (**p < 0.01).
Mentions: Aβ42 is the predominant species of Aβ in the AD brain and this peptide concentration will increase more than other Aβ species as AD progresses353637. At 26 weeks, there was no significant difference in the Aβ42/Aβ40 ratio (Fig. 1) between APP, ApoE3xAPP and ApoE4xAPP mice. However, at 78 weeks, post-hoc analysis Tukey-Kramer analysis showed that ApoE4xAPP mice had significantly higher Aβ42/ Aβ40 ratio than APP and ApoE3xAPP mice (Fig. 1).

Bottom Line: Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration.However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons.Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

View Article: PubMed Central - PubMed

Affiliation: Departments of Physiology Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer's disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein (APP) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among APP, ApoE3xAPP and ApoE4xAPP mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in APP and ApoE4xAPP mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

No MeSH data available.


Related in: MedlinePlus