Abstract
BackgroundImpaired 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.MethodsMale 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.ResultsAll 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.
Highlights
The concept that impaired insulin signalling influences neurodegenerative mechanisms in Alzheimer’s disease (AD) and leads to impairment in cognitive processes is attracting increasing attention
The risk of AD is highest amongst APOEe4 carriers with type 2 diabetes mellitus (T2DM) [14] and neuropathological studies reported the highest number of AD lesions in brain tissue of e4 diabetic patients [14]
Insulin resistance was induced by feeding APOE mice a high (60%) fat diet (HFD), or low (10%) fat diet (LFD) for 32 weeks
Summary
The concept that impaired insulin signalling influences neurodegenerative mechanisms in Alzheimer’s disease (AD) and leads to impairment in cognitive processes is attracting increasing attention This hypothesis was prompted by the clinical investigations showing the reduction of glucose utilisation in the AD brain [1]. The risk of AD is highest amongst APOEe4 carriers with T2DM [14] and neuropathological studies reported the highest number of AD lesions in brain tissue of e4 diabetic patients [14]. 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 APOEe3 or e4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment
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