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1.
Sci Rep ; 4: 6580, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25301084

ABSTRACT

The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.


Subject(s)
Aging/genetics , Apolipoprotein E4/genetics , Memory/physiology , Receptors, LDL/biosynthesis , Tumor Suppressor Proteins/biosynthesis , Aging/physiology , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Female , Gene Expression Regulation, Developmental , Humans , Low Density Lipoprotein Receptor-Related Protein-1 , Mice , Mice, Transgenic , Neurons/metabolism , Neurons/pathology , Phosphorylation , Protein Isoforms , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction
2.
FEBS Open Bio ; 4: 260-5, 2014.
Article in English | MEDLINE | ID: mdl-24649407

ABSTRACT

The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

3.
Sci Rep ; 4: 3754, 2014 Jan 17.
Article in English | MEDLINE | ID: mdl-24435134

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.


Subject(s)
Apolipoprotein E4/genetics , Brain/metabolism , Insulin Receptor Substrate Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Apolipoprotein E4/deficiency , Blood Glucose , Cholesterol/blood , Cholesterol/metabolism , Gene Expression , Gene Targeting , Glucose/metabolism , Humans , Insulin/blood , Insulin/metabolism , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinases/metabolism , Receptor, Insulin/genetics , Receptor, Insulin/metabolism
4.
Biochem Biophys Res Commun ; 437(4): 642-7, 2013 Aug 09.
Article in English | MEDLINE | ID: mdl-23872114

ABSTRACT

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and this can be contributed by aberrant metabolic enzyme function. But, the mechanism causing this enzymatic impairment is unclear. Amyloid precursor protein (APP) is known to be alternatively spliced to produce three major isoforms in the brain (APP695, APP751, APP770). Both APP770 and APP751 contain the Kunitz Protease Inhibitory (KPI) domain, but the former also contain an extra OX-2 domain. APP695 on the other hand, lacks both domains. In AD, up-regulation of the KPI-containing APP isoforms has been reported. But the functional contribution of this elevation is unclear. In the present study, we have expressed and compared the effect of the non-KPI containing APP695 and the KPI-containing APP751 on mitochondrial function. We found that the KPI-containing APP751 significantly decreased the expression of three major mitochondrial metabolic enzymes; citrate synthase, succinate dehydrogenase and cytochrome c oxidase (COX IV). This reduction lowers the NAD(+)/NADH ratio, COX IV activity and mitochondrial membrane potential. Overall, this study demonstrated that up-regulation of the KPI-containing APP isoforms is likely to contribute to the impairment of metabolic enzymes and mitochondrial function in AD.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Gene Expression Regulation , Mitochondria/metabolism , Peptide Fragments/metabolism , Alzheimer Disease/metabolism , Cell Line , Citrate (si)-Synthase/metabolism , DNA, Complementary/metabolism , Electron Transport Complex IV/metabolism , Humans , Membrane Potential, Mitochondrial , Mutation , Plasmids/metabolism , Protein Interaction Domains and Motifs , Succinate Dehydrogenase/metabolism , Up-Regulation
5.
Biochem Biophys Res Commun ; 424(3): 482-7, 2012 Aug 03.
Article in English | MEDLINE | ID: mdl-22776200

ABSTRACT

Studies have shown similarities between the histopathological characteristics of NPC and Alzheimer's disease (AD) including amyloid and tau pathologies. While dysfunction in insulin signaling was widely detected in AD brain, the function of insulin signaling proteins has not been examined in NPC disease. In this study, we have examined the expression and phosphorylation of proteins linked to the insulin signaling pathway in the brain of 9 weeks old NPC(nih) mice. Our results showed lower expression of insulin receptor substrate 2 (IRS2) in the NPC(nih) mice, and insulin receptor substrate 1 (IRS1) expression was almost non-detectable in this NPC mouse model. This reduction was associated with the loss of expression for the regulatory p85 subunit of phosphatidylinositol 3-kinase (p85/PI3K). Interestingly, the impairment was observed to link to a greater reduction of Akt phosphorylation at residue T308 than S473. This aberrant Akt phosphorylation could be contributing to lower GSK3ß phosphorylation detected in the NPC(nih) mouse brain. To our knowledge, this is the first report documenting impaired insulin signaling in the brain of a NPC mouse model.


Subject(s)
Insulin/metabolism , Niemann-Pick Disease, Type C/metabolism , Animals , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Disease Models, Animal , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Insulin Receptor Substrate Proteins/biosynthesis , Mice , Mice, Inbred BALB C , Mice, Mutant Strains , Niemann-Pick Disease, Type C/genetics , Phosphorylation , Signal Transduction
6.
J Alzheimers Dis ; 29(4): 783-91, 2012.
Article in English | MEDLINE | ID: mdl-22337827

ABSTRACT

Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer's disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-ß (Aß) biogenesis is unclear. In this study using female AßPPsw/PS1ΔE9 mice, we found that the level of Aß40 was fairly constant in 6- to 15-month-old brains, whereas Aß42 was only significantly increased in the 15-month-old brain. In contrast, increased levels of IRß, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AßPPsw/PS1ΔE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aß42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AßPPsw/PS1ΔE9 mouse brain. Furthermore, the expression profile of IRß, IRS-2, and p85/PI3K in AßPPsw/PS1ΔE9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in AßPPsw/PS1ΔE9 mice.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Insulin/metabolism , Peptide Fragments/metabolism , Signal Transduction/physiology , Age Factors , Alzheimer Disease/pathology , Amyloid beta-Peptides/blood , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Densitometry , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Regulation/genetics , Glucose/metabolism , Glucose Transport Proteins, Facilitative/genetics , Glucose Transport Proteins, Facilitative/metabolism , Humans , Mice , Mice, Transgenic , Mutation/genetics , Peptide Fragments/blood , Presenilin-1/genetics , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Signal Transduction/genetics
7.
J Neurochem ; 112(6): 1619-26, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20070866

ABSTRACT

Neurodegeneration is the final cause of death in Niemann-Pick Type C (NPC) disease, a cholesterol-storage disorder. Accumulating evidence indicates that NPC may share common pathological mechanisms with Alzheimer's disease, including the link between aberrant cholesterol metabolism and amyloid-beta (Abeta) deposition. Apolipoprotein E (apoE) is highly expressed in the brain and plays a pivotal role in cholesterol metabolism. ApoE can also modulate Abeta production and clearance, and it is a major genetic risk factor for Alzheimer's disease. Although apoE is glycosylated, the functional significance of this chemical alteration on Abeta catabolism is unclear. In this study using an NPC animal model, we detect specific changes in apoE glycosylation that correlate with increased Abeta(42) accumulation prior to the appearance of neurological abnormalities. This suggests that increased apoE expression could be a compensatory response to the increased Abeta(42) deposition in NPC(nih) mice. We also observe what appears to be a simplification of the glycosylation process on apoE during neurodegeneration.


Subject(s)
Amyloid beta-Peptides/metabolism , Apolipoproteins E/metabolism , Gene Expression Regulation/physiology , Niemann-Pick Disease, Type C/metabolism , Peptide Fragments/metabolism , Age Factors , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Apolipoproteins E/genetics , Brain/pathology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay/methods , Gene Expression Regulation/genetics , Glycosylation , Intracellular Signaling Peptides and Proteins , Lectins/metabolism , Mice , Mice, Inbred BALB C , Mice, Transgenic , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/pathology , Peptide Fragments/genetics , Polysaccharides/metabolism , Proteins/genetics
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