Brain Cholesterol: Long Secret Life Behind a Barrier

Abstract

Abstract-Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450 -generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far.In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed. Key Words: brain cholesterol Ⅲ blood-brain barrier Ⅲ cholesterol 24S-hydroxylase Ⅲ Alzheimer disease Ⅲ statins H ighly sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the body. There is a distinct difference between the situation in the central nervous system and that in most other extrahepatic tissues. Outside the brain, the cellular needs for cholesterol is covered by de novo synthesis and by cellular uptake of lipoprotein cholesterol from the circulation. In the brain, the blood-brain barrier effectively prevents uptake from the circulation, and de novo synthesis is responsible for practically all cholesterol present in this organ. The independence of the isolated pool of cholesterol in the brain is likely to reflect a high need for constancy in the cholesterol content of membrane and myelin, a constancy that would be difficult to keep if brain cholesterol had been exchangeable with lipoprotein cholesterol.The importance of cholesterol in the nervous system was recognized as early as 1834, when Couerbe's observations lead him to regard cholesterol as un element principal of the nervous system. 1 Despite concerted efforts in the interim, it is only during the past few decades that the brain has begun to surrender the secrets of the behavior of one of its most abundant lipids.In the present brief review, we summarize the basal characteristics of brain cholesterol and some recent findings with respect to homeostasis of this compound in the brain. Emphasis is put on the newly described relation betwee...

Cholesterol enhances classical conditioning of the rabbit heart rate response

“…A recent report has also shown that feeding cholesterol to young, normal rats improves learning in the Morris water maze (Dufour, Liu, Gusev, Alkon, & Atzori, 2006). Given that dietary cholesterol does not cross the blood brain barrier in any appreciable amount (Bjorkhem & Meaney, 2004;Dietschy & Turley, 2001;Dietschy & Turley, 2004;Tuma & Hubbard, 2003), it remains to be determined how heart rate conditioning, which is controlled in part by the amygdala via the dorsal motor nucleus of the vagus, was increased as a result of a cholesterol-rich diet. The same would be true for the effects of cholesterol on rat water maze learning (Dufour et al, 2006) and previous research showing that addition of cholesterol to the diet of animals deficient in cholesterol or animals that have cholesterol synthesis blocked reverses learning and memory deficits (Endo, Nishimura, & Kimura, 1996;O'Brien et al, 2002;Voikar, Rauvala, & Ikonen, 2002;Xu et al, 1998).…”

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

“…Adding to this unique lipid environment is the synthesis of cholesterol within the brain, predominantly in glial cells, without significant import from the liver 3. Neuronal cholesterol is dysregulated in AD, and persistent neuronal damage response may increase cholesterol biosynthesis 4.…”

Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

“…The early expression of Xdhcr7 is in accordance with the multiple developmental defects reported in DHCR7 mutations (Porter, 2000;Waterham and Wanders, 2000;Nowaczyk and Waye, 2001;WitschBaumgartner et al, 2001;Ciara et al, 2004), since the reported phenotypes may result from a failure of early patterning events. Accumulating data support the idea that the human brain depends for the most part on de novo synthesised cholesterol, owing to the selectivity of the blood-brain barrier (Muenke and Cohen, 2000;Turley, 2001, 2004;Woollett, 2001;Herz and Bock, 2002;Pfrieger, 2003b;Waage-Baudet et al, 2003;Bjorkhem and Meaney, 2004). In tadpoles, Xdhcr7 expression is prominent in brain structures (Fig.…”