One hypothesis is that the formation of C-terminal EX 527 truncated fragments by neuron-specific cleavage of the apoE4 protein escapes through the secretory pathway, enters the cytosol and interacts with mitochondria via its hydrophobic lipid-binding region. This leads to perturbation of mitochondrial function and hence diminishes mitochondrial participation in glycolytic processes. Via the same route apoE4 truncated fragments can also induce tau phosphorylation, as shown in vivo and in vitro. Since a direct role of PPARc agonism is to Sorafenib abmole stimulate mitochondrial biogenesis, this suggests that perhaps neurotoxic C-terminal fragments in our APOEe4 mice caused excessive damage to mitochondria in neurons. Accordingly, APOEe4 mice did not respond to pioglitazone like APOEe3 mice. A higher dose of pioglitazone may possibly overcome the detrimental effects of apoE4 we observed. According to the amyloid cascade hypothesis of AD, it is the formation or deposition of Ab that initiates the formation of neurofibrillary tangles. We examined the levels of soluble Ab40 and Ab42 by ELISA and also the processing of APP by western blotting in our insulin resistant animals with and without pioglitazone treatment. Surprisingly, we found no changes in APOE knock in animals. Our findings oppose the findings by two studies; Ho et al., who found diet-induced insulin resistance promoted generation of Ab40 and Ab42 in the brain of Tg2576 mice and from a very recent study which found apoE isoform dependent effects on Ab levels in PDAPP mice. In both of these studies by Ho et al., and Bales et al., the use of APP transgenic animals predisposes the animals to amyloid pathology. This may allow both authors to detect an effect with diet or APOE genotype, which we failed to find. In our HFD fed APOE KO animals we detected a trend of higher levels of soluble Ab40 and Ab42 in comparison to animals with the APOE gene. The idea that APOE KOs cannot clear Ab from brain has been suggested and implies that the clearance of Ab from the brain to the periphery requires apoE and is mediated by transport of apoE-Ab complexes across the BBB via LRP-1. Further, our results did not replicate the finding of reduction in Ab levels following pioglitazone treatment, as reported in two earlier in vivo studies using Tg2576 mice and APPV717l mice. This is most likely due to different mouse models and/or diet may play a part in the formation of Ab species. Numerous studies have reported the role of apoE in the periphery, in our study we report for the first time the combined effect of apoE and insulin in the brain in vivo. Our data therefore suggests that in our APOE model of diet-induced T2DM, tau phosphorylation arises due to some process downstream of Ab.