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

APOE mice develop diet-induced T2DM- like insulin resistance.Plasma insulin levels were measured in APOE KO, APOEε3, APOEε4 and WT mice over 32 weeks of feeding with A) LFD and B) HFD. Blood samples from the tail vein at each OGTT were collected and plasma was analysed for insulin by ELISA. Values are mean±SEM, n = 10–12. In A) plasma insulin levels in all LFD animals reached *p<0.05 by t-test compared to WT mice. In B) plasma insulin levels in HFD fed animals reached *p<0.05 or ***p<0.001 by t-test compared to WT mice as indicated. Significance is indicated by * APOE KO, + APOEε3, ∧ APOEε4.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3037394&req=5

pone-0016991-g003: APOE mice develop diet-induced T2DM- like insulin resistance.Plasma insulin levels were measured in APOE KO, APOEε3, APOEε4 and WT mice over 32 weeks of feeding with A) LFD and B) HFD. Blood samples from the tail vein at each OGTT were collected and plasma was analysed for insulin by ELISA. Values are mean±SEM, n = 10–12. In A) plasma insulin levels in all LFD animals reached *p<0.05 by t-test compared to WT mice. In B) plasma insulin levels in HFD fed animals reached *p<0.05 or ***p<0.001 by t-test compared to WT mice as indicated. Significance is indicated by * APOE KO, + APOEε3, ∧ APOEε4.

Mentions: Hyperglycaemia was accompanied by elevations in plasma insulin. At baseline all groups of mice had similar levels of insulin (Figure 3). At the end of the 32 weeks study, all the HFD group of animals had statistically significantly elevated levels of plasma insulin compared to the LFD group, with the highest in APOEε4 (5.9±0.5 µg/l), followed by APOEε3 (5.2±0.6 µg/), APOE KO (4.8±0.5 µg/l) and then WT (3.5±0.6 µg/l) (Figure 3B). Within each APOE genotype and between the LFD and HFD fed animals, insulin levels reached a significant difference by 6 weeks of diet. In contrast, insulin levels in the LFD fed animals increased by only a small amount (Figure 3A).


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)

APOE mice develop diet-induced T2DM- like insulin resistance.Plasma insulin levels were measured in APOE KO, APOEε3, APOEε4 and WT mice over 32 weeks of feeding with A) LFD and B) HFD. Blood samples from the tail vein at each OGTT were collected and plasma was analysed for insulin by ELISA. Values are mean±SEM, n = 10–12. In A) plasma insulin levels in all LFD animals reached *p<0.05 by t-test compared to WT mice. In B) plasma insulin levels in HFD fed animals reached *p<0.05 or ***p<0.001 by t-test compared to WT mice as indicated. Significance is indicated by * APOE KO, + APOEε3, ∧ APOEε4.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0016991-g003: APOE mice develop diet-induced T2DM- like insulin resistance.Plasma insulin levels were measured in APOE KO, APOEε3, APOEε4 and WT mice over 32 weeks of feeding with A) LFD and B) HFD. Blood samples from the tail vein at each OGTT were collected and plasma was analysed for insulin by ELISA. Values are mean±SEM, n = 10–12. In A) plasma insulin levels in all LFD animals reached *p<0.05 by t-test compared to WT mice. In B) plasma insulin levels in HFD fed animals reached *p<0.05 or ***p<0.001 by t-test compared to WT mice as indicated. Significance is indicated by * APOE KO, + APOEε3, ∧ APOEε4.
Mentions: Hyperglycaemia was accompanied by elevations in plasma insulin. At baseline all groups of mice had similar levels of insulin (Figure 3). At the end of the 32 weeks study, all the HFD group of animals had statistically significantly elevated levels of plasma insulin compared to the LFD group, with the highest in APOEε4 (5.9±0.5 µg/l), followed by APOEε3 (5.2±0.6 µg/), APOE KO (4.8±0.5 µg/l) and then WT (3.5±0.6 µg/l) (Figure 3B). Within each APOE genotype and between the LFD and HFD fed animals, insulin levels reached a significant difference by 6 weeks of diet. In contrast, insulin levels in the LFD fed animals increased by only a small amount (Figure 3A).

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