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P1‐162: The effects of pioglitazone on tau phosphorylation in apoE models of insulin resistance
Author(s) -
To Alvina W.M.,
Ribe Elena M.,
Schroeder Joern E.,
Lovestone Simon
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.712
Subject(s) - pioglitazone , insulin resistance , medicine , endocrinology , apolipoprotein e , insulin , insulin receptor , diabetes mellitus , peroxisome proliferator activated receptor , type 2 diabetes , population , type 2 diabetes mellitus , biology , receptor , disease , environmental health
Background: Insulin resistance precedes type II diabetes mellitus (T2DM) and T2DM is associated with Alzheimer’s disease (AD). Impairment in the insulin signaling pathway has been increasingly reported to contribute to the pathogenesis of AD. The e4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for DM. Neuropathological studies assessing the hallmarks of AD in relation to the copy number of the e4 isoform amongst the diabetic population have produced conflicting reports. The thiazolidinediones (TZD) are potent peroxisome proliferator-activated receptor gamma (PPARg) agonists, peripheral insulin sensitizers, clinically prescribed to T2DM patients. In a recent clinical trial 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 tau pathology in apoE models of insulin resistance and whether pioglitazone reversed tau pathology in an apoE-dependent manner. Methods: We used animal models of insulin resistance with different apoE backgrounds. Animals 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 on this diet animals were divided into treatment or vehicle groups. Treatment group were orally dosed with pioglitazone (20mg/kg) whilst vehicle group received 1% methylcellulose. Metabolic changes were assessed. Brains were removed for biochemical analyses. Results: All animals fed on a HFD developed hyperglycaemia accompanied by elevations of plasma insulin. Western blotting showed tau phosphorylation reduced at 3 epitopes (Ser396, Thr231 and Ser202/Thr205) in all animals on HFD compared to LFD animals, there being no differences between apoE genotypes. However, introduction of pioglitazone to HFD animals lead to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in apoE3 animals only, the reverse in apoE4 mice was observed. Conclusions: In our model of T2DM, results suggest that insulin resistance causes tau phosphorylation independently of apoE genotype. However, pioglitazone treatment lowers tau phosphorylation via an apoE isoform specific effect with the human apoE3 isoform being most responsive to treatment.