Papers by Dieter Lütjohann
Journal of Lipid Research, 2002
Cholesterol is implicated to play a role in Alzheimer disease pathology. Therefore, the concentra... more Cholesterol is implicated to play a role in Alzheimer disease pathology. Therefore, the concentrations of cholesterol, its precursors, and its degradation products in brain homogenates of aging wild-type and  -amyloid precursor protein transgenic mice carrying the Swedish mutation (APP23) were analyzed. Among the sterols measured, lanosterol is the first common intermediate of two different pathways, which use either desmosterol or lathosterol as the predominant precursors for de novo synthesis of brain cholesterol. In young mice, cholesterol is mainly synthesized via the desmosterol pathway, while in aged mice, lathosterol is the major precursor. 24 S -hydroxycholesterol (cerebrosterol), which plays a key role in the removal of cholesterol from the brain, modestly increased during aging. No differences in the levels of cholesterol, its precursors, or its metabolites were found between wild-type and APP23 transgenic mice. Moreover, the levels of the exogenous plant sterols campesterol and sitosterol were significantly elevated in the brains of APP23 animals at age 12 and 18 months. This time point coincides with abundant plaque formation. -Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain. J. Lipid Res. 2002Res. . 43: 1078Res. -1085 Supplementary key words Alzheimer disease • brain cholesterol metabolism • neurodegeneration • oxysterols • plant sterols Abbreviations: AD, Alzheimer disease; APP,  -amyloid precursor protein; BBB, blood-brain-barrier; 4, epsilon 4; GC-MS, gas chromatography-mass spectrometry; 24 S -OH-Chol, 24 S -hydroxycholesterol; TMSi, trimethylsilyl.
Steroids, 2004
Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reducta... more Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reductase, so-called statins, are effective in lowering the prevalence of Alzheimer's disease. Whether the effect of statins is due to a local inhibition of cholesterol synthesis in the brain or whether it is mediated by the reduced levels of cholesterol in the circulation is not known. In the present work, we tested the possibility that high doses of lipophilic and hydrophilic statins, simvastatin and pravastatin, respectively, or a diet high in cholesterol could affect cholesterol homeostasis in the brain of guinea pigs. The total brain cholesterol levels were not affected by high-dose simvastatin or pravastatin treatment. Significantly lower levels of the cholesterol precursor lathosterol and its ratio to cholesterol were found in the brains of simvastatin and pravastatin-treated animals. 24S-Hydroxycholesterol, the transportable form of cholesterol across the blood-brain barrier, was significantly lower in the brain of pravastatin-treated animals. Excessive cholesterol feeding resulted in higher serum cholesterol levels but did not affect total brain cholesterol level. However, de novo cholesterol synthesis in the brain seemed to be down-regulated, as indicated by lower absolute levels and cholesterol-related ratios of lathosterol compared with controls. The passage of deuterium-labeled cholesterol across the blood-brain barrier in one animal was found to be approximately 1%. Our results suggest that brain cholesterol synthesis in guinea pigs can be slightly, but significantly, influenced by high doses of lipophilic and hydrophilic statins as well as by high dietary cholesterol intake, while total brain cholesterol content and thus, cholesterol homeostasis is maintained.
Neuroscience Letters, 2000
The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we... more The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6±10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (243%, P , 0:001). Patients with advanced Alzheimer's disease and cerebral in¯ammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not signi®cantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no signi®cant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the¯ux of 24S-hydroxycholesterol from the brain. q
Neuroreport, 2000
The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into t... more The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into the periphery is probably an important step for the maintenance of brain cholesterol homeostasis. Recent findings suggest that plasma 24S-hydroxycholesterol may be elevated in Alzheimer's disease (AD) and vascular dementia at least at some stage of the disease, suggesting increased brain cholesterol turnover during neurodegeneration. We investigated whether plasma 24S-hydroxycholesterol concentrations depend on the severity of AD and on the apolipoprotein E (apoE) genotype. Severity of AD and inheritance of the apoE4 allele were independently associated with reduced plasma 24S-hydroxycholesterol/cholesterol ratios. The results suggest that the decrease of plasma 24S-hydroxycholesterol/cholesterol in severely affected AD patients is a peripheral marker for loss of cholesterol 24S-hydroxylase in the CNS. Inheritance of the apoE4 allele may be associated with increased apoE-mediated transport of brain cholesterol to the periphery or with decreased activity of the 24S-hydroxylase. Longitudinal studies will assess the validity of the ratio plasma 24S-hydroxycholesterol/cholesterol as a state marker for AD.
We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circ... more We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages ( r 2 ؍ 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain. -Bretillon, L., D. Lütjohann, L. Ståhle, T. Widhe, L. Bindl, G. Eggertsen, U. Diczfalusy, and I. Björkhem. Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J. Lipid Res. 2000. 41: 840-845.
Neurobiology of Disease, 2006
The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptid... more The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (AB) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3 -4 months beginning at a young adult age (6 months). Hippocampal AB levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased AB levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on AB production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level. D
Neuroscience Letters, 2002
Experiments in cell cultures indicate that accumulation of cholesterol in hippocampal neurons res... more Experiments in cell cultures indicate that accumulation of cholesterol in hippocampal neurons results in an accelerated cleavage of amyloid precursor protein into amyloidogenic components. To be eliminated from the brain, cholesterol is converted to 24S-hydroxycholesterol which may reflect cerebral cholesterol turnover. We investigated cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol in a group of 14 Alzheimer's disease (AD) patients and ten healthy controls without any cognitive deficits or psychiatric or neurological disorders. To exclude potential effects of circulating plasma cholesterol on CSF 24S-hydroxycholesterol levels, only patients and controls with cholesterol levels in the normal range of 150-230 mg/dl were included. We found significantly elevated 24S-hydroxycholesterol CSF but not plasma levels in AD patients compared with healthy controls. Our results demonstrate that CSF 24S-hydroxycholesterol is increased in AD. This effect does not seem to be triggered by plasma cholesterol levels since the latter did not significantly differ between groups. q
Pharmacogenetics and Genomics, 2005
The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake... more The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake transporter OATP1B1, influence the short-term effects of pravastatin on cholesterol synthesis. We determined plasma concentrations of lathosterol and cholesterol up to 12 h after intake of a single dose of 40 mg pravastatin in 41 healthy Caucasian subjects, in whom SLCO1B1 single nucleotide polymorphisms (SNP; 521T>C and -11187G>A) and haplotypes (*15B and *17) had been previously shown to be associated with considerably elevated plasma pravastatin levels. The effects of pravastatin on plasma lathosterol concentration and lathosterol to cholesterol concentration ratio, which are established markers of the rate of cholesterol synthesis in vivo, were significantly smaller among the three heterozygous carriers of the SLCO1B1 *17 haplotype (containing the -11187G>A, 388A>G and 521T>C SNPs) as compared with non-carriers. Significant inverse relationships were found between pravastatin area under the concentration-time curve (AUC) values and effects of pravastatin on lathosterol and lathosterol to cholesterol ratio among the whole study population. These results suggest that uptake of pravastatin into hepatocytes is impaired in carriers of the SLCO1B1 haplotype *17, resulting in higher plasma pravastatin concentrations but lower concentrations of pravastatin in hepatocytes and thereby in a smaller inhibitory effect on cholesterol synthesis. The cholesterol-lowering response to pravastatin may be impaired in carriers of the *17 haplotype.
Background: An elevation of total CSF tau protein has been consistently shown even m very mild Al... more Background: An elevation of total CSF tau protein has been consistently shown even m very mild Alzheimer's disease (AD). However, there is a considerable overlap between AD and healthy controls. Objective: We measured total CSF tau and tau phosphorylated at threonine 231 to compare diagnostic accuracy in discriminating between AD patients, healthy controls (HC), and subjects at risk for developing dementia with AD pathology. Methods: A total of IO0 samples collected at two centers was analyzed: 39 AD-patients. 41 HC-subjects, 9 non-demented patients with Down's syndrome (NDDown), and I I patients with mild cognitive impairment (MCI. progressive amnesic type without dementia). CSF phospho-tau and total tau were measured by enzyme-linked immunosorbent assays (ELISA). For total tau, we used a commercially available ELISA (Innogenetics). Phospho-tnu was measured by a newly developed ELISA specific for tau phosphorylated at threonine 231. Results: Levels of phospho-tau and total tau were significantly different between AD and HC (p<O.OOl). However, phospho-tau showed a better discriminative power. Using a ROC-analysis, under the constraint to maximize the sum of specificity and sensitivity within the given sample, phospho-tau (total tau) discriminated with a sensitivity of 97.4% (91.9%) and a specificity of 92.7% (78.3%) between AD and HC subjects. Applying the cutoffs found by ROC-analysis, 7/9 NDDown and 8/l I MCI subjects thawed elevated phospho-tau and total tau levels. Conclusion: In an independent ample, we could confirm our previous results on the high power of phospho-tau in discriminating between AD and HC subjects. Additionally, diagnostic accuracy was considerably greater using phospho-tau than total tau. Finally, the markers were mcreased in subjects at risk indicating their potential value in detecting the presence of AD pathology before clinical onset of dementia.
We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol i... more We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lütjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be ؊ 10.2 ؎ 2.8 ng/ml (mean ؎ SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 ؎ 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/ 24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain.-Björkhem, I., D. Lütjohann, U. Diczfalusy, L. Ståhle, G. Ahlborg, and J. Wahren. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J. Lipid Res. 1998. 39: 1594-1600.
Brain Research, 1999
Neurodegenerative disorders are characterized by a massive loss of nerve cells. The neuronal cell... more Neurodegenerative disorders are characterized by a massive loss of nerve cells. The neuronal cell death is accompanied by an increased cholesterol release and conversion of cholesterol into the polar metabolite, 24-hydroxycholesterol (24-OH-Chol), appears to be an important mechanism in the central nervous system for eliminating cholesterol from the brain. We tested the influence of 24-OH-Chol on SH-SY5Y human neuroblastoma cells by recording cell morphology, Trypan blue exclusion, LDH-release into the culture medium, intracellular calcium and reactive oxygen species (ROS). The exposure of SH-SY5Y human neuroblastoma cells to 50 microM 24-OH-Chol led to a 90% loss in cell viability within 30 h, the LDH-release into the medium increased rapidly after 24 h, and after 24 to 30 h we found an elevation in intracellular calcium. These results show that, in a physiological concentration range, 24-OH-Chol damages neuronal cells, thus we speculate that this oxysterol may be involved in the etiology of neurodegenerative disease.
Journal of Lipid Research, 2003
24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuousl... more 24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S-and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production.
American Journal of Cardiology, 2005
The recent discovery of transporters in the intestinal mucosa and the canalicular membrane has gi... more The recent discovery of transporters in the intestinal mucosa and the canalicular membrane has given new insights into the regulation of intestinal absorption as well as the biliary output of cholesterol and plant sterols. The 2 adenosine triphosphate (ATP)-binding cassette (ABC) half-transporters ABCG5 and ABCG8 are expressed in the mucosa cells and the canalicular membrane, and they resecrete sterols, especially absorbed plant sterols, back into the intestinal lumen and from the liver into bile. Defects of either of these cotransporters lead to the rare inherited disease of phytosterolemia, which is clinically defined by hyperabsorption and diminished biliary excretion of plant sterols. Furthermore, it has been recently demonstrated that the Niemann-Pick C1-Like 1 (NPC1L1) transporter is most likely responsible for the transport of cholesterol and plant sterols from the brush border membrane into the intestinal mucosa. Ezetimibe interferes with NPC1L1, reducing the intestinal uptake of cholesterol and plant sterols. These new findings contribute to our understanding of cholesterol and plant sterol concentrations in serum, and the effect of dietary and drug intervention to reduce serum concentrations of sterols.
Clinical Pharmacology & Therapeutics, 2005
BackgroundMyopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition... more BackgroundMyopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.MethodsForty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.ResultsThe ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 ± 7.1 nmol/g to 41.2 ± 27.0 nmol/g in the simvastatin group and from 22.6 ± 8.6 nmol/g to 40.0 ± 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 ± 13.6 nmol/g to 26.4 ± 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 ± 7.1 nmol/g to 41.2 ± 27.0 nmol/g in the simvastatin group and from 22.6 ± 8.6 nmol/g to 40.0 ± 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 ± 13.6 nmol/g to 26.4 ± 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.ConclusionsHigh-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.Clinical Pharmacology & Therapeutics (2005) 78, 60–68; doi: 10.1016/j.clpt.2005.03.006High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.Clinical Pharmacology & Therapeutics (2005) 78, 60–68; doi: 10.1016/j.clpt.2005.03.006
Neurobiology of Aging, 2003
Increased formation of the -amyloid peptide (A) is a central event in the pathogenesis of Alzhe... more Increased formation of the -amyloid peptide (A) is a central event in the pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes A formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.
Journal of Lipid Research, 2003
The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitoste... more The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitosterolemia suggests that intestinal uptake of cholesterol is an unselective process, and that discrimination between cholesterol and plant sterols takes place at the level of sterol efflux from the enterocyte. Although plant sterols are structurally very similar to cholesterol, differing only in their side chain length, they are absorbed from the intestine to a markedly lower extent. In order to further evaluate the process of discrimination, three different sterols (cholesterol, campesterol, sitosterol) and their corresponding 5 ␣ -stanols (cholestanol, campestanol, sitostanol) were compared concerning their concentration in the proximal small intestine, in serum, and in bile after a single oral dose of deuterated compounds. The data obtained support the hypothesis that i ) the uptake of sterols and stanols is an extremely rapid process, ii ) discrimination probably takes place on the level of reverse transport back into the gut lumen, iii ) plant stanols are taken up, but not absorbed to a measurable extent, and iv ) the process of discrimination probably also exists at the level of biliary excretion. The range of structural alterations that decrease intestinal absorption and increase biliary excretion is: 1 ) campesterol, 2 ) cholestanol-sitosterol, and 3 ) campestanol-sitostanol. -Igel, M., U. Giesa, D. Lütjohann, and K. von Bergmann. Comparison of the intestinal uptake of cholesterol, plant sterols, and stanols in mice. J. Lipid Res. 2003. 44: 533-538.
Molecular Psychiatry, 2002
Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycho... more Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24Shydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C → T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A → G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C → T polymorphism was associated with an increased 24Shydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24Shydroxycholesterol/cholesterol ratio in the brain. Molecular Psychiatry (2002) 7, 899-902.
Uploads
Papers by Dieter Lütjohann