AbstractsBiology & Animal Science

BACKGROUND: Alzheimer s disease (AD) is a severe neurodegenerative disease that mainly afflicts elderly persons, with a characteristic progressive decline of cognitive functions and dementia. It is believed that the majority of all AD patients are affected by the sporadic form, thus caused by the combined effects of several risk factors, such as elevated cholesterol levels in midlife and deficiencies in the lipoprotein transporters apolipoprotein E (ApoE). Cholesterol play an essential role in the central nervous system (CNS) were it maintains normal physiological conditions, and is a requirement for the ability of neurons to communicate. It has previously been demonstrated that the cholesterol homeostasis in the CNS is maintained by a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol, with a net flux of 27-hydroxycholesterol from the circulation into the brain. The importance of a preserved cholesterol homeostasis has been supported by the observation that dietary cholesterol may induce an inflammation in the CNS, and increase the levels of pro-inflammatory mediators. It has, in direct association with these observations, been demonstrated that plasma levels of pro-inflammatory proteins, such as interleukin-6, are increased before the clinical onset of AD, after which a chronic state of inflammation often is found. Accordingly, it has been suggested that memory and cognitive functions could benefit from a cholesterol-lowering therapy. STUDIES: The research presented in this thesis has examined the effect of cholesterol and cholesterol-lowering therapy with rosuvastatin, on key factors associated with AD. The experimental setup consisted of in vitro-models with human neuroblastoma SH-SY5Y cells (paper I II), and in vivo-models with wild type (WT) and ApoE knockout (ApoE-/-) mice, provided with high levels of dietary cholesterol for 18 weeks (paper III IV). The hydrophilic compound rosuvastatin is an effective inhibitor of cholesterol synthesis and has been demonstrated to be an effective treatment for hypercholesterolemia, with an indirect effect on microglial activation and inflammation through isoprenoid depletion. RESULTS: Paper I describes the selective non-amyloidogenic processing (alpha-secretase activity) of the amyloid precursor protein (APP), induced by 24(S)-hydroxycholesterol, with a subsequent increased ratio of alpha-/beta-secretase activity, and increased levels of soluble APPalpha and total soluble sAPP; effects significantly decreased by the presence of 27-hydroxycholesterol. Paper II describes the effect of pre-treating in vitro-cultures with rosuvastatin prior exposure to Abeta oligomers. The treatment was found to decrease caspase-3 activity and promote cell survival, with a selective non-amyloidogenic processing of APP. However, no influence was observed on cell viability, with a potential explanation in a downregulated metabolism. Paper III IV describes the effect of high levels of dietary cholesterol in vivo, with increased microglial activation in WT mice, increased gliosis in…