ABSTRACT
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-ß 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.
Subject(s)
Alzheimer Disease , Dietary Supplements , Disease Models, Animal , Seaweed , Animals , Alzheimer Disease/drug therapy , Seaweed/chemistry , Mice , Hippocampus/drug effects , Hippocampus/metabolism , Plant Extracts/pharmacology , Mice, Transgenic , Sargassum/chemistry , Humans , Plaque, Amyloid , Cholesterol/metabolism , Cholesterol/blood , Male , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , tau Proteins/metabolismABSTRACT
The nuclear liver X receptors (LXRα/ß) 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/ß- 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.
Subject(s)
Alzheimer Disease , Seaweed , Mice , Animals , Liver X Receptors/genetics , Liver X Receptors/metabolism , Alzheimer Disease/drug therapy , PPAR alpha/genetics , Tandem Mass Spectrometry , Receptors, Cytoplasmic and Nuclear/genetics , Cholesterol/metabolism , Fatty Acids/metabolismABSTRACT
The nuclear receptors-liver X receptors (LXR α and ß) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/ß activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3ß-hydroxychol-5-en-24-oate (S1), methyl (3ß)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3ß,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.
Subject(s)
Neurodegenerative Diseases , Phytosterols , Humans , Liver X Receptors , Sterols/pharmacology , Orphan Nuclear Receptors/genetics , Hydroxycholesterols , Neurodegenerative Diseases/drug therapy , CholesterolABSTRACT
We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRß-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-ß (Aß) 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 APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 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, Aß 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 APPswePS1ΔE9 mice without affecting the Aß plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 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 APPswePS1ΔE9 mice independent of effects on Aß 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.
Subject(s)
Alzheimer Disease/drug therapy , Anti-Inflammatory Agents/pharmacology , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cognition/drug effects , Nootropic Agents/pharmacology , Stigmasterol/analogs & derivatives , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Animals , Calcium-Binding Proteins/metabolism , Cell Line, Tumor , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Mice, Transgenic , Microfilament Proteins/metabolism , Microglia/drug effects , Microglia/metabolism , Recognition, Psychology/drug effects , Stigmasterol/pharmacologyABSTRACT
Edible marine algae, or seaweeds, are a rich source of several bioactive compounds including phytosterols, carotenoids, and polysaccharides. Over the last decades, seaweed-derived constituents turned out to not only reside in the systemic circulation, but are able to cross the blood-brain barrier to exert neuro-active functions both in homeostatic and pathological conditions. Therefore, seaweed-derived constituents have gained increasing interest for their neuro-immunomodulatory and neuroprotective properties, rendering them interesting candidates for the management of several neurodegenerative disorders. In particular seaweed-derived phytosterols gained interest for the treatment of neurodegenerative disorders as they potentiate neuroplasticity, enhance phagocytic clearance of neurotoxic peptides and have anti-inflammatory properties. Though, the anti-inflammatory and anti-oxidative properties of other constituents including carotenoids, phenols and polysaccharides have recently gained more interest. In this review, we provide an overview of a selection of the described neuro-active properties of seaweed-derived constituents with a focus on phytosterols.
