96 research outputs found
Brain cholesterol in normal and pathological aging
Aberrations in cerebral cholesterol homeostasis can lead to severe neurological diseases. Recent findings strengthen the link between brain cholesterol metabolism and factors involved in synaptic plasticity, a process essential for learning and memory functions, as well as regeneration, which are affected in Alzheimer's Disease (AD). Cholesterol homeostasis within the brain is independent of that in the rest of the body and needs to be strictly regulated for optimal brain functioning. In contrast with what was initially assumed brain cholesterol homeostasis can be modulated by extra-cerebral factors. We have found that enhancement of the cholesterol-turnover in the brain by administration of the synthetic activator of liver x receptos (LXRs), T0901317, leads to restoration of memory functions in an AD mouse-model.Memory in C57Bl6NCrl mice was not further improved by the same treatment. Moreover, it was found that in contrast with cholesterol, the structurally very similar dietary derived plant sterols can enter the brain. Plant sterols may be natural activators of LXRs. Evide
Phosphodiesterase Type 4 Inhibition in CNS Diseases
Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABU). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects
Methylglyoxal-Derived Advanced Glycation Endproducts Accumulate in Multiple Sclerosis Lesions
Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs. 154 ± 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS
Limited daily feeding and intermittent feeding have different effects on regional brain energy homeostasis during aging.
Albeit aging is an inevitable process, the rate of aging is susceptible to modifications. Dietary restriction (DR) is a vigorous nongenetic and nonpharmacological intervention that is known to delay aging and increase healthspan in diverse species. This study aimed to compare the impact of different restricting feeding regimes such as limited daily feeding (LDF, 60% AL) and intermittent feeding (IF) on brain energy homeostasis during aging. The analysis was focused on the key molecules in glucose and cholesterol metabolism in the cortex and hippocampus of middle-aged (12-month-old) and aged (24-month-old) male Wistar rats. We measured the impact of different DRs on the expression levels of AMPK, glucose transporters (GLUT1, GLUT3, GLUT4), and the rate-limiting enzyme in the cholesterol synthesis pathway (HMGCR). Additionally, we assessed the changes in the amounts of cholesterol, its metabolite, and precursors following LDF and IF. IF decreased the levels of AMPK and pAMPK in the cortex while the increased levels were detected in the hippocampus. Glucose metabolism was more affected in the cortex, while cholesterol metabolism was more influenced in the hippocampus. Overall, the hippocampus was more resilient to the DRs, with fewer changes compared to the cortex. We showed that LDF and IF differently affected the brain energy homeostasis during aging and that specific brain regions exhibited distinct vulnerabilities towards DRs. Consequently, special attention should be paid to the DR application among elderly as different phases of aging do not respond equally to altered nutritional regimes.This is a post-peer-review, pre-copyedit version of an article published in Biogerontology. The final authenticated version is available online at: [http://dx.doi.org/10.1007/s10522-018-9743-y
Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds:A Potential Application in Alzheimer’s Disease?
The nuclear liver X receptors (LXRα/β) and peroxisome proliferator-activated receptors (PPARα/γ) are involved in the regulation of multiple biological processes, including lipid metabolism and inflammation. The activation of these receptors has been found to have neuroprotective effects, making them interesting therapeutic targets for neurodegenerative disorders such as Alzheimer's Disease (AD). The Asian brown seaweed Sargassum fusiforme contains both LXR-activating (oxy)phytosterols and PPAR-activating fatty acids. We have previously shown that dietary supplementation with lipid extracts of Sargassum fusiforme prevents disease progression in a mouse model of AD, without inducing adverse effects associated with synthetic pan-LXR agonists. We now determined the LXRα/β- and PPARα/γ-activating capacity of lipid extracts of six European brown seaweed species ( Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, Himanthalia elongata, Saccharina latissima, and Sargassum muticum) and the Asian seaweed Sargassum fusiforme using a dual luciferase reporter assay. We analyzed the sterol and fatty acid profiles of the extracts by GC-MS and UPLC MS/MS, respectively, and determined their effects on the expression of LXR and PPAR target genes in several cell lines using quantitative PCR. All extracts were found to activate LXRs, with the Himanthalia elongata extract showing the most pronounced efficacy, comparable to Sargassum fusiforme, for LXR activation and transcriptional regulation of LXR-target genes. Extracts of Alaria esculenta, Fucus vesiculosus, and Saccharina latissima showed the highest capacity to activate PPARα, while extracts of Alaria esculenta, Ascophyllum nodosum, Fucus vesiculosus, and Sargassum muticum showed the highest capacity to activate PPARγ, comparable to Sargassum fusiforme extract. In CCF-STTG1 astrocytoma cells, all extracts induced expression of cholesterol efflux genes ( ABCG1, ABCA1, and APOE) and suppressed expression of cholesterol and fatty acid synthesis genes ( DHCR7, DHCR24, HMGCR and SREBF2, and SREBF1, ACACA, SCD1 and FASN, respectively). Our data show that lipophilic fractions of European brown seaweeds activate LXRs and PPARs and thereby modulate lipid metabolism. These results support the potential of brown seaweeds in the prevention and/or treatment of neurodegenerative diseases and possibly cardiometabolic and inflammatory diseases via concurrent activation of LXRs and PPARs. </p
24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer's Disease
We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXR beta-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-beta (A beta) deposition in an Alzheimer's disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1 Delta E9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1 Delta E9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1 Delta E9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, A beta and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1 Delta E9 mice without affecting the A beta plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1 Delta E9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1 Delta E9 mice independent of effects on A beta load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline
Dietary advanced glycation endproducts (AGEs) increase their concentration in plasma and tissues, result in inflammation and modulate gut microbial composition in mice; evidence for reversibility
Scope: Dietary advanced glycation endproducts (AGEs) are associated with negative biological effects, possibly due to accumulation in plasma and tissues and through modulation of inflammation and gut microbiota. Whether these biological consequences are reversible by limiting dietary AGE intake is unknown. Methods and results: Young healthy C57BL/6 mice were fed a standard chow (n = 10) or a baked chow high AGE-diet (n = 10) (~1.8–6.9 fold increased protein-bound Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl) lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) for 10 weeks or a switch diet with baked chow for 5 weeks followed by 5 weeks of standard chow (n = 10). We assessed accumulation of AGEs in plasma, kidney, and liver and measured inflammatory markers and gut microbial composition. After 10 weeks of baked chow, a substantial panel of AGEs were increased in plasma, liver, and kidney. These increases were normalized after the switch diet. The inflammatory z-score increased after the baked chow diet. Gut microbial composition differed significantly between groups, with enriched Dubosiella spp. dominating these alterations. Conclusion: A high AGE-diet led to an increase of AGEs in plasma, kidney, and liver and to more inflammation and modification of the gut microbiota. These effects were reversed or discontinued by a diet lower in AGEs.Peer reviewe
Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment
Abstract Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease
Supplementation of Seaweed Extracts to the Diet Reduces Symptoms of Alzheimer's Disease in the APPswePS1ΔE9 Mouse Model
We previously demonstrated that diet supplementation with seaweed Sargassum fusiforme (S. fusiforme) prevented AD-related pathology in a mouse model of Alzheimer's Disease (AD). Here, we tested a lipid extract of seaweed Himanthalia elongata (H. elongata) and a supercritical fluid (SCF) extract of S. fusiforme that is free of excess inorganic arsenic. Diet supplementation with H. elongata extract prevented cognitive deterioration in APPswePS1ΔE9 mice. Similar trends were observed for the S. fusiforme SCF extract. The cerebral amyloid-β plaque load remained unaffected. However, IHC analysis revealed that both extracts lowered glial markers in the brains of APPswePS1ΔE9 mice. While cerebellar cholesterol concentrations remained unaffected, both extracts increased desmosterol, an endogenous LXR agonist with anti-inflammatory properties. Both extracts increased cholesterol efflux, and particularly, H. elongata extract decreased the production of pro-inflammatory cytokines in LPS-stimulated THP-1-derived macrophages. Additionally, our findings suggest a reduction of AD-associated phosphorylated tau and promotion of early oligodendrocyte differentiation by H. elongata. RNA sequencing on the hippocampus of one-week-treated APPswePS1ΔE9 mice revealed effects of H. elongata on, amongst others, acetylcholine and synaptogenesis signaling pathways. In conclusion, extracts of H. elongata and S. fusiforme show potential to reduce AD-related pathology in APPswePS1ΔE9 mice. Increasing desmosterol concentrations may contribute to these effects by dampening neuroinflammation.</p
Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model
Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer's disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXR beta. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal A beta plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRa activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of A beta 42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of A beta. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXR beta activation.</p
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