Mateos, L. (Laura)
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- Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism(American Society for Biochemistry and Molecular Biology, 2011) Ismail, M.A. (Muhammad Al-Mustaf); Heverin, M. (M.); Gil-Bea, F.J. (Francisco J.); Schöls, L. (Ludger); Cedazo-Minguez, A. (Ángel); Folkesson, R. (R.); Schüle, R. (Rebecca); Björkhem, I. (Ingemar); Mateos, L. (Laura)Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.
- Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro(Wiley Blackwell, 2009) Akterin, S. (Susanne); Flores-Morales, A. (Amílcar); Rahman, A. (Atiqur); Gil-Bea, F.J. (Francisco J.); Cedazo-Minguez, A. (Ángel); Spulber, S. (Stefan); Björkhem, I. (Ingemar); Schultzberg, M. (Marianne); Mateos, L. (Laura)Growing evidence strongly suggests that high fat diet (HFD) has an important role in some neurodegenerative disorders, including Alzheimer's disease (AD). To identify new cellular pathways linking hypercholesterolemia and neurodegeneration, we analyzed the effects of HFD on gene expression in mouse brain. Using cDNA microarrays and real time RT-PCR, we found that HFD has a mild, but significant effect on the expression of several genes. The altered genes include molecules linked to AD pathology and others of potential interest for neurodegeneration. We further investigated the effect of HFD on the activity-regulated cytoskeleton-associated protein (Arc). Expression of Arc was decreased in cerebral cortex and hippocampus of HFD-fed animals. From the known regulatory mechanisms of Arc expression, HFD reduced N-methyl-D-aspartate receptor (NMDAR) activity, as seen by decreases in tyrosine phosphorylation of NMDAR2A and levels of NMDAR1. Additionally, we demonstrated that 27-hydroxycholesterol, a cholesterol metabolite that enters the brain from the blood, decreases Arc levels as well as NMDAR and Src kinase activities in rat primary hippocampal neurons. Finally, we showed that Arc levels are decreased in the cortex of AD brains. We propose that one of the mechanisms, by which hypercholesterolemia contributes to neurodegenerative diseases, could be through Arc down-regulation caused by 27-hydroxycholesterol.
- Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation(Wiley-Blackwell, 2011) Ramirez, M.J. (María Javier); Solas, M. (Maite); Winblad, B. (Bengt); Gil-Bea, F.J. (Francisco J.); Cedazo-Minguez, A. (Ángel); Mateos, L. (Laura)Recent evidence suggests that activity-regulated cytoskeleton associated protein (Arc) and brain-derived neurotrophic factor (BDNF) are key players in the cellular mechanisms that trigger synaptic changes and memory consolidation. Cholinergic deafferentiation of hippocampus has been largely shown to induce memory impairments in different behavioral tasks. However, the mechanisms underlying cholinergic-induced memory formation remain unclear. The role of hippocampal cholinergic denervation on synaptic consolidation and further acquisition of spatial memory was hereby examined by analyzing Arc and BDNF in standard environment and after behavioral training in Morris water maze (MWM). In standard environment, a cholinergic hypofunction induced by the toxin (192) IgG-saporin led to significant decreases in Arc protein and mRNA as well as in BDNF. Lesioned rats subjected to MWM showed a worse acquisition performance that was reversed after galantamine treatment. Recovery of memory acquisition was accompanied by normalization of Arc and BDNF levels in hippocampus. Stimulation of muscarinic, but not nicotinic receptors, in hippocampal primary neurons caused a rapid induction of Arc production. These data suggest that cholinergic denervation of hippocampus leads to deficits in muscarinic-dependent induction of Arc and a subsequent impairment of spatial memory acquisition. © 2010 Wiley-Liss, Inc.
- Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease(IOS Press, 2011) Ismail, M.A. (Muhammad Al-Mustaf); Winblad, B. (Bengt); Gil-Bea, F.J. (Francisco J.); Cedazo-Minguez, A. (Ángel); Leoni, V. (Valerio); Björkhem, I. (Ingemar); Mateos, L. (Laura)In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs. Here we show that the levels of angiotensinogen (AGT) and ACE are increased in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. Moreover, we show ACE activity in the CSF to be positively correlated with both plasma and CSF levels of 27-hydroxycholesterol (27-OH), an oxysterol known to pass through the BBB and taken up from the circulation by the brain. In addition, treatment of rat primary neurons, astrocytes, and human neuroblastoma cells with 27-OH resulted in increased production of AGT. Our results demonstrate that upregulation of renin-angiotensin system (RAS) in AD brains occurs not only at the enzymatic level (ACE) but also at the substrate level (AGT). The possibility that 27-OH is part of a mechanism linking hypercholesterolemia with increased brain RAS activity and increased AD risk is discussed.