Studies on apolipoprotein E and high cholesterol diet as risk factors for neurodegeneration

Sammanfattning: Elevated level of plasma cholesterol is a well-established risk factor for cardiovascular disease, and emerging evidence suggest that it plays a role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). The relations between dietary habits and neurodegeneration are complex, as the brain is selectively separated from peripheral circulation by the blood brain barrier (BBB). Brain cholesterol is mostly independent from dietary uptake or hepatic synthesis and is almost completely synthesized in situ. The enzymatic conversion of cholesterol into 24S-hydroxycholesterol, which fluxes across the BBB into the circulation is the recognized pathway for the elimination and the homeostasis maintenance of brain cholesterol. Apolipoprotein E (apoE) is the major cholesterol transporter in the central nervous system (CNS). From the three human isoforms of apoE (E2, E3 and E4), the presence of apoE4 is the most important known genetic risk factor for sporadic AD and it has also been linked to many other forms of neurodegeneration. The mechanisms by which apoE4 increases the risk for neurodegeneration are largely unknown, but it has been hypothesised that apoE4 may have a deficient function compared with other isoforms. In general, there is a lack of knowledge of how different risk factors affect neurodegenerative disorders, and also of the possible synergistic effect of several risk factors contributing together to these processes. The work presented in this thesis aims to investigate the mechanisms involving apoE and high cholesterol (HQ diet in neurodegenerative processes. As a model we used wild type (WT) and apoE deficient mice on normal diet or HC diet for 9 months. We have found that HC diet stimulates glial activation and increases expression of IL-6 and caspase-1, and that these effects are potentiated by the apoE deficiency (papers I and II). HC diet also upregulates the expression of antioxidant enzyme NQO1 (paper I). In addition, we found that the combination of HC diet and apoE deficiency induces tau hyperphosphorylation and increases the activity of several tau kinases in the brain (paper III). Finally, we used cDNA microarrays to explore the effects of HC diet on brain gene expression. We found that a high cholesterol intake affects the expression of several genes involved in neurodegeneration (paper IV). The present study give insight to the molecular mechanisms by which HC diet and lack of apoE increase the risk for neurodegeneration and suggest that several risk factors may act synergically in these processes.