Deciphering the role of 27-hydroxycholesterol in neurodegeneration

Sammanfattning: Cholesterol is constantly attributed to neurodegenerative diseases including Alzheimer’s disease (AD). This is due to the association of high blood cholesterol and the consequences of cholesterol metabolism in these conditions. However the brain isolates itself from the peripheral cholesterol with the use of its impervious barrier, therefore how does cholesterol influence the brain? Converted into the oxidized form known as 27-hydroxycholesterol (27-OH), extracerebral cholesterol is able to circumvent this blood brain barrier and enter the brain’s refuge. Some studies point to the effect of this oxysterol on brain cells, indicating that this metabolite is more than a cholesterol intermediate. Herein, we dissect the role this cholesterol metabolite undertakes in the brain both in vitro and in vivo , while probing its influence on neurodegenerative diseases. In Paper I we elucidated the levels of 27-OH in both the cerebrospinal fluid (CSF) and plasma of mild cognitively impaired (MCI) and AD patients. In addition to correlating it to AD markers, we further investigated its relationship with the angiotensin-converting enzyme (ACE), which was increased in AD as previously described. Delving deeper uncovered 27-OH had more of a causal link than a mere correlation with the renin-angiotensin system (RAS) in the brain highlighted in Paper I and Paper II. This system, apart from being independent from the renal system, is involved in many processes in the brain including learning and memory. The repercussions of 27-OH on the brain RAS was further investigated in vivo in Paper II, in mice lacking the ability to produce 27-OH, and in humans. Furthermore, the effects of 27-OH were also observed in mice fed a high-fat diet, a connection that is further investigated in all the papers within this thesis. These results draw to attention the relationship between plasma cholesterol, hypert ension and neurodegeneration. In addition to affecting the spatial memory of mice, 27-OH reduced the levels of glucose uptake in their brains. Emphasized in Paper III, the mechanistic link between 27-OH and glucose metabolism was examined, explicating several therapeutic targets. The biomarker suitability of 27-OH was tested in a small proof of concept study utilizing 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET). Results illustrated a negative correlation, thus having higher levels of 27-OH in the CSF is associated with lower glucose uptake levels in the brain of individuals with ramifications on memory. Inflammation is an important part of AD and is thought to occur very early in the disease progression. Moreover, peripherally 27-OH plays a part in mediating atherosclerosis via its proinflammatory actions. To this end, we hypothesized that 27-OH may have similar actions in the brain and the resulting data is presented in Paper IV. 27-OH increased the levels of the inflammatory mediat or S100A8 in addition to its receptor, Receptor for Advanced Glycation Endproduct (RAGE) and the downstream β-secretase 1 (BACE1) observed in several mice models. S100A8 was previously described by us to be increased in the brains of AD mice models and may accumulate even before amyloid plaque formation. This study therefore accentuates the function of 27-OH in propagating inflammation in the brain, a function recognized peripherally. Neurodegenerative diseases such as AD are debilitating conditions affecting the lives of millions; however to this date the causes of these overwhelming disorders remains unclear. While the levels of CSF 27-OH are likely to be increased in many AD patients, little is known as to the ramifications of this increase. Herein, we try to bridge this gap and propose several mechanistic links between blood cholesterol and neurodegenerative diseases while underscoring several plausible therapeutic targets, in an attempt to further empower our fight against AD.