Cholesterol synthesis rate in human hippocampus declines with aging

Neuroscience Letters 403 (2006) 15–19

Cholesterol synthesis rate in human hippocampus declines with aging K.M. Thelen a , P. Falkai b , T.A. Bayer b , D. L¨utjohann a,∗ a

Department of Clinical Pharmacology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany b Department of Psychiatry, Saarland University Medical Center, Kirrberger Strasse, D-66421 Homburg, Germany Received 9 March 2006; received in revised form 13 April 2006; accepted 15 April 2006

Abstract During the last three to four decades, interest in the interaction of circulating and brain cholesterol has increased. As the CNS matures and cholesterol pools in the brain become constant, the rate of de novo synthesis of cholesterol in the brain is expected to decline. We measured cholesterol, its precursors and its brain specific metabolite 24S-hydroxycholesterol in hippocampus from 7 female and 13 male corpses by highly sensitive and specific gas chromatography–mass spectrometry. Two age groups (young, n = 10; elderly, n = 10) were formed with a cut-off at the median age of 38 years. The amount of cholesterol was comparable in young and elderly subjects. The concentrations of the cholesterol precursors lanosterol and lathosterol were significantly higher in young (P = 0.036 and 0.005, respectively) than in elderly subjects. In accordance, there was a significantly negative correlation between age and lathosterol concentrations (r = −0.505; P = 0.023). Absolute levels of 24S-hydroxycholesterol in the brain were slightly, but not significantly, lower in the hippocampal specimens from the elderly subjects. We conclude that during aging, cholesterol synthesis is decreased in the hippocampus, while absolute cholesterol content remains at a stable level. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Brain cholesterol; Lanosterol; Lathosterol; Desmosterol; 24S-hydroxycholesterol; Oxysterols

In recent years, interest in brain cholesterol metabolism has grown tremendously since this sterol has been identified to play a crucial role in certain neurodegenerative diseases like Alzheimer disease or Niemann-Pick type C disease [11]. Cholesterol is the major lipid compound of the brain accounting for approximately 25%, while whole body cholesterol makes up just about 2%. The supply of brain cholesterol is covered by in situ de novo synthesis and there is limited efflux across the blood–brain barrier. The half life of brain cholesterol has been estimated to be 6 months [1] and cholesterol is recycled and redistributed during neuronal growth and constitution via apolipoprotein E (ApoE). ApoE is the major vehicle for cholesterol transport in the brain where it is released by astrocytes and glia [11,44]. There are two different sources of brain cholesterol: neuronal membranes and myelin. It has been estimated that up to 70% of the brain cholesterol is associated to myelin [26]. In contrast to myelin, neuronal membranes are far more resistant during brain aging in females and males [54]. Myelin, which forms axons in the CNS, is reduced during aging [9,17] and the age-related loss of myelin function has been shown to negatively impact

∗

Corresponding author. Tel.: +49 228 287 5272; fax: ++49 228 287 6094. E-mail address: [email protected] (D. L¨utjohann).

0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.04.034

cognitive performance in primates [41] and humans [38,57]. Neurons lose the ability of cholesterol biosynthesis after birth and astrocytes and glia cells take on this function [12]. A study by Mauch et al. indicated that the ability of CNS neurons to form synapses is limited by the availability of cholesterol. In their study, cholesterol was identified as synapse-promoting factor secreted by glia cells in ApoE-containing lipoproteins [34]. The lack of cholesterol supply in neurons of hippocampal slices caused the failure of neurotransmission and synaptic plasticity [25]. Further, survival and growth of neuronal cells is promoted by the addition of cholesterol and impaired by inhibition of cholesterol synthesis [35]. These and other studies provide evidence that cholesterol plays an important role in CNS development and synaptic plasticity [42]. The elimination of cholesterol mainly occurs after conversion into a side-chain oxidized oxysterol, 24S-hydroxycholesterol (24S-OH-Chol) [3,30]. 24S-OH-Chol is formed by an enzyme denoted CYP46A1, which, in humans, has been shown to be exclusively present in neurons [29]. This oxysterol is a ligand for the nuclear liver X receptors (LXR) ␣ and ␤ which are expressed in the brain and which coordinately regulate genes involved in cholesterol homeostasis [28,40]. Mice fed an LXR agonist had increased gene expression of the ATP binding cassette transporter (ABC) A1 in hippocampus [62]. ABCA1 is a

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K.M. Thelen et al. / Neuroscience Letters 403 (2006) 15–19

cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins [37]. It has been estimated that approximately 6–7 mg of cholesterol is eliminated daily from the human brain via 24S-OH-Chol [3,30] and 1–2 mg via ApoE [5]. 24Shydroxycholesterol has also been identified as a possible marker for neurodegeneration [39] and thus, is an indicator of brain cholesterol homeostasis in the circulation [4,32]. Lanosterol is the first sterol formed during cholesterol biosynthesis by conversion of squalene [7,10,15]. The choice of pathway is determined by the stage at which the double bond at position C24 in the sterol side chain is reduced [22]. If the double bond is retained until the last reaction, cholesterol synthesis proceeds via desmosterol (Bloch pathway), whereas early reduction leads to the formation of lathosterol and 7-dehydrocholesterol (Kandutsch-Russel pathway). In humans, lathosterol is regarded as a plasma surrogate marker for whole body cholesterol synthesis [23]. Here, we regard the cholesterol precursors lanosterol, desmosterol and lathosterol as tissue markers of local cholesterol synthesis and 24S-hydroxycholesterol as a marker for cholesterol degradation. The study was performed on hippocampus from 20 individuals (7 female and 13 male), who, until death, led a normal social life with no history of neurological or psychiatric disease, and who died suddenly and unexpectedly. The autopsy material used in this study covered the life period between 18 and 86 years of age. Two age groups were created for reason of comparison of sterol content and synthesis rate and degradation of cholesterol in the hippocampus, respectively. The mean value of age of the subjects was 46 years (±22 S.D.). The median of subjects’ age was 38 years and this was used to divide the subjects into two age groups. In the following, the two groups are denoted as young and elderly group, to distinguish between both age groups. Characteristics of the individuals in the two groups are shown in Table 1. The brains were obtained with written consent from the relatives and stored in the brain bank of the Saarland University, Department of Psychiatry, which is a center of Brainnet Germany, funded by the German Research Council (previously located in Bonn, Germany). The project was approved by the Bonn University Human Subjects Committee (Ethical Committee). Specimens were reviewed by a neuropathologist and found to be free of neurological disease. Frozen samples from the hippocampus were dissected and shock frozen for further processing. The dissected hippocampus specimens were dried to constant weight in a Speedvac® (Savant instruments Inc., NY, USA).

Table 2 Concentration of sterols in hippocampus of individuals in the young (n = 10) and the elderly group (n = 10) Young group (<38 years) Cholesterola Lathosterolb Lanosterolb Desmosterolb 24S-OH-Cholb

106.5 148.4 10.4 62.2 154.9

± ± ± ± ±

15.1 33.4** 2.0* 9.0 27.2

Elderly group (>38 years) 108.0 108.4 7.9 57.6 132.5

± ± ± ± ±

Data is expressed as mean ± SD. * p < 0.05 compared to elder group. ** p < 0.01 compared to elder group. a ␮g/mg dry weight. b ng/mg dry weight.

Cholesterol, its precursors lanosterol, lathosterol, desmosterol and its metabolite 24S-hydroxycholesterol were extracted from dried hippocampus tissues by chloroform/methanol (2:1 (v/v)) and determined after derivatization to the corresponding trimethylsilyethers by gas chromatography-flame ionization detection and gas chromatography–mass spectrometry (GC–MS) as reported previously [56]. The TMSi-ether of lanosterol was measured at m/z 393 (M+ –OTMSi–CH3 ) and that of desmosterol at m/z 441 (M+ –CH3 ). All statistical procedures were performed using the Statistical Package of the Social Sciences (SPSS 12.0; SPSS Inc., Chicago, Illinois, USA). The unpaired t-test was performed to analyze differences between the two age groups. Correlation analysis was performed with a Pearson’s correlation coefficient. Data are expressed as mean ± standard deviation (S.D.). P-values less than 0.05 were considered statistically significant. Sterol concentrations are given in Table 2. There was no gender difference in any sterol concentration. The amount of total cholesterol in hippocampus specimen was comparable in young and elderly subjects. The concentrations of the cholesterol precursors lanosterol and lathosterol were significantly higher in young (P = 0.036 and 0.005, respectively) than in elderly subjects. In accordance, there was a significant negative correlation between age and lathosterol concentrations (r = −0.505, P = 0.023; Fig. 1). Lathosterol levels correlated significantly with lanosterol levels (r = 0.729, P < 0.001). The levels of the brain specific cholesterol metabolite 24S-hydroxycholesterol did not differ in the two age groups. The median age of the subjects was chosen to compare and investigate age-dependent differences in cholesterol synthesis

Table 1 Sex, age and brain weight of individuals in the young (median age 31; n = 10) and the elderly group (median age 60; n = 10)

Sex (f/m) Age (year; minimum–maximum) Brain weight (g)

Young group (<38 years)

Elderly group (>38 years)

4/6 30 ± 6 (18–36) 1378 ± 136

3/7 63 ± 20 (40–86) 1284 ± 133

Data is expressed in mean ± standard deviation.

15.5 21.9 2.7 20.0 31.7

Fig. 1. Correlation between lathosterol and age in hippocampus.

K.M. Thelen et al. / Neuroscience Letters 403 (2006) 15–19

and degradation according to the finding that there is an agerelated increase in whole brain cholesterol levels to a peak reached in the forth decade of life [47]. To our knowledge, the presented results, for the first time, provide insight that the de novo synthesis of cholesterol but not the cholesterol amount itself declines with aging in human hippocampus. The absence of an effect on desmosterol concentrations as well as the high correlation between the lanosterol and lathosterol levels indicate, that the “desmosterol or Bloch-pathway” plays a minor role in the formation of CNS cholesterol during aging as was found in mice [31]. However, mice lacking cholesterol have been generated successfully and survived to adulthood. In these mice, desmosterol levels were remarkably elevated and accounted for 99% of total sterols, suggesting that this precursor is able to take on the function of cholesterol [61]. In humans, the failure of forming cholesterol out of desmosterol causes desmosterolosis. This severe disease is characterized by elevated desmosterol levels and a grave impact on CNS development [60]. The pool of whole brain cholesterol is resistible, as the supply must be warranted. In accordance with a previous study [53], we did not find an age-dependent change in the absolute amount of cholesterol in the hippocampus. However, some studies suggested that brain cholesterol content decreases to a moderate extent during aging [55,66]. Cholesterol synthesis rate is significantly higher in younger subjects possibly implying higher hippocampus activity regarding brain development and learning. During maturation and brain aging, the different cell compounds undergo profound changes. For instance, in a postmortem study in humans, myelin lipids were lost early and the loss exceeded 40% at 100 years of age [54]. During aging, several oligodendrocytes lose their ability to produce cholesterol and thus provide the need for cholesterol for myelinization. It has been proposed that the impairment of cholesterol synthesis or lipoprotein transport diminishes synaptic plasticity, and possibly thereby cognitive functions such as learning and memory [6,33]. Surprisingly, the cholesterol content of the exofacial leaflet of synaptic plasma membranes doubles with age [19,63]. In general, an increase in cholesterol amounts in plasma membranes in the aging brain involves a decrease in membrane fluidity [52]. Mental activities, such as learning, decrease with age [13,50], which by itself is accompanied by an increase in cholesterol [48]. Moreover, cholesterol overload of neuronal cells leads to neurotoxicity. Likewise, A␤ oligomer production, a hallmark of Alzheimer disease [16,51], is promoted by high cholesterol content of lipid bilayers [14,65]. Apolipoproteins, such as ApoD, E, and J, take on cholesterol transport to neurons [2,21,45] and are synthesized by oligodendrocytes. When lipoproteins are removed from culture medium, an upregulation of cholesterol synthesis has been shown in different glia culture preparations [27,59]. Interestingly, in rat experiments, loss of cholesterol synthesis coincided with a peak in hippocampus ApoE expression [46]. In the present study, we were unable to measure or detect lipoproteins. However, the finding that cholesterol synthesis decreases with age accompanied by constant levels of

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total cholesterol indicates that, under normal conditions, the apolipoprotein trafficking processes do not seem to be impaired, thus guaranteeing cholesterol supply where it is needed. Trafficking of cholesterol may be due to increasing amounts of free cholesterol from degraded myelin, e.g. impairment or an existing misregulation possibly resulting in neurodegenerative processes in the brain [43]. Likewise, the ApoE4 isoform is associated with an increased risk of late-onset Alzheimer disease and is less able to promote neurite outgrowth than other ApoE isoforms [36]. The elimination of cholesterol in the brain mainly happens via CYP46A1-induced oxidation to 24S-hydroxycholesterol. In this study, we found a slight but not significant reduction of the levels of 24S-hydroxycholesterol. However, there was a tendency to an age-dependent decrease of 24S-OH-Chol in hippocampus. It is likely that, during aging, the activity of CYP46A1 decreases due to reduced ability to fulfill the need of neuronal integrity [64] or due to neurodegenerative changes [5] with a reduced number of functional neurons in aged tissues. It has been reported that in patients with Alzheimer disease, the levels of 24S-OH-Chol are decreased in certain brain areas [18], whereas in normal subjects, its plasma concentrations seem to remain constant during aging [30]. Presumably, the decrease of 24S-OH-Chol levels in the brain may also protect against increasing loss of cholesterol. It was assumed that neurons release 24S-OH-Chol as a consequence of excess load with cholesterol and thereby provide negative feedback to cholesterol synthesizing astrocytes [43]. As 24SOH-Chol is a ligand for LXR, the decrease of 24S-OH-Chol might prevent enhanced efflux of cholesterol. Moreover, evidence has been gained from in vitro experiments that elevated levels of 24S-OH-Chol provoke neurotoxicity [24]. However, it is presumable that cholesterol metabolism in the different regions of the brain is not uniform [20] and several studies support the existence of regional and cell-specific differences in cholesterol content [66], lipoprotein transporter and receptor distribution [8] as well as the expression of cholesterol synthesizing enzymes [49]. Moreover, it has been shown previously that brain volume decreases with age and is accompanied by memory decline [58]. It is beyond question that age is affecting the brain and that it constitutes a major risk factor for the development of neurodegenerative diseases such as Alzheimer disease. Hence, cholesterol metabolism in the CNS is a fundamental field of investigation and its role in brain pathology has to be further elucidated. Acknowledgement We thank Silvia Friedrichs for her skilful technical assistance. References [1] M. Andersson, P.G. Elmberger, C. Edlund, K. Kristensson, G. Dallner, Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices, FEBS Lett. 269 (1990) 15–18.

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