Limits...
The ε3 and ε4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice.

To AW, Ribe EM, Chuang TT, Schroeder JE, Lovestone S - PLoS ONE (2011)

Bottom Line: Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype.The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only.We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Institute of Psychiatry, London, United Kingdom.

ABSTRACT

Background: Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD). The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM). Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.

Methods: Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD) or low fat diet (LFD) for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.

Results: All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

Show MeSH

Related in: MedlinePlus

Levels of soluble Aβ40 and Aβ42 in HFD fed mice treated with or without pioglitazone.Aβ A) x-40 and B) x-42 was analysed by ELISA in the frontal cortex of APOE mice fed HFD and with or without pioglitazone treatment. *p<0.05 by t-test.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3037394&req=5

pone-0016991-g006: Levels of soluble Aβ40 and Aβ42 in HFD fed mice treated with or without pioglitazone.Aβ A) x-40 and B) x-42 was analysed by ELISA in the frontal cortex of APOE mice fed HFD and with or without pioglitazone treatment. *p<0.05 by t-test.

Mentions: Pioglitazone treatment has been shown to lower amyloid load in animal models [33], [38]. In our study, APOE KO animals fed a HFD showed a trend for higher levels of soluble Aβ40 and Aβ42 compared to all other APOE genotypes (Figure 6). No effects of pioglitazone were observed in relation to Aβ42 at any genotype. No effects of pioglitazone on Aβ40 were observed in either WT or APOEε3 or APOEε4 animals but there was a significant reduction in APOE KO animals. We note however that APOE KO animals had a particularly high Aβ40 level pre-treatment and this may represent regression to the mean in a single genotype.


The ε3 and ε4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice.

To AW, Ribe EM, Chuang TT, Schroeder JE, Lovestone S - PLoS ONE (2011)

Levels of soluble Aβ40 and Aβ42 in HFD fed mice treated with or without pioglitazone.Aβ A) x-40 and B) x-42 was analysed by ELISA in the frontal cortex of APOE mice fed HFD and with or without pioglitazone treatment. *p<0.05 by t-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037394&req=5

pone-0016991-g006: Levels of soluble Aβ40 and Aβ42 in HFD fed mice treated with or without pioglitazone.Aβ A) x-40 and B) x-42 was analysed by ELISA in the frontal cortex of APOE mice fed HFD and with or without pioglitazone treatment. *p<0.05 by t-test.
Mentions: Pioglitazone treatment has been shown to lower amyloid load in animal models [33], [38]. In our study, APOE KO animals fed a HFD showed a trend for higher levels of soluble Aβ40 and Aβ42 compared to all other APOE genotypes (Figure 6). No effects of pioglitazone were observed in relation to Aβ42 at any genotype. No effects of pioglitazone on Aβ40 were observed in either WT or APOEε3 or APOEε4 animals but there was a significant reduction in APOE KO animals. We note however that APOE KO animals had a particularly high Aβ40 level pre-treatment and this may represent regression to the mean in a single genotype.

Bottom Line: Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype.The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only.We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Institute of Psychiatry, London, United Kingdom.

ABSTRACT

Background: Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD). The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM). Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.

Methods: Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD) or low fat diet (LFD) for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.

Results: All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

Show MeSH
Related in: MedlinePlus