Insulin resistance, part of the metabolic syndrome, is associated with type 2 diabetes mellitus (T2DM) and increased risk for Alzheimer’s disease (AD). The e4 allele of APOE is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for T2DM. The thiazolidinediones (TZDs), PPARy agonists, are peripheral insulin sensitisers used to treat T2DM and have been found to slow cognitive decline in mild to moderate AD patients. Since it is not yet clear how PPARy affect insulin signalling processes in AD, I investigated the effects of the TZD, pioglitazone, on Ap metabolism and tau phosphorylation in high fat diet (HFD)-induced insulin resistant mice carrying the human APOEeS or APOEe4 genes. HFD reduced tau phosphorylation at specific epitopes, independent of APOE genotype. Pioglitazone treatment reduced tau phosphorylation, in an APOE-dependent manner, with the APOEeS mice being most responsive. Examination of HFD effects on the cortical transcriptome revealed increased expression of the ABCA1 gene in mice lacking APOE and the ADRA2A gene in APOEe4 mice. ABCA1 and apoE are associated with Ap clearance in the brain, while ADRA2A suppresses insulin secretion and polymorphisms in this gene is associated with T2DM risk. Erk1/2, p38, JNK, and calcineurin were differentially expressed between APOEeS and APOEe4 mice on HFD indicating these kinases and phosphatases may contribute to the increased risk for AD imparted by APOEe4. I have identified APOE allele-dependent effects of PPARy agonists on tau phosphorylation and have identified diet and APOE allele-dependent effects on gene expression that relate to AD. Further work is needed to validate current findings and to further elucidate the mechanism. A better understanding of the relative importance of brain and peripheral insulin resistance will greatly improve our understanding of the disease process and also aide the rational design of therapeutics to halt its progression.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:631279 |
| Date | January 2012 |
| Creators | To, Alvina |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/functional-interactions-between-peroxisome-proliferator-activated-receptorgamma-and-polipoprotein-e-isoforms-in-the-regulation-of-neural-functions-in-models-of-insulin-resistancerelevance-to-alzheimers-disease(cd60b6c8-8161-4447-b58c-553cb2e19f16).html |
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