1. Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model.
- Author
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Bogie J, Hoeks C, Schepers M, Tiane A, Cuypers A, Leijten F, Chintapakorn Y, Suttiyut T, Pornpakakul S, Struik D, Kerksiek A, Liu HB, Hellings N, Martinez-Martinez P, Jonker JW, Dewachter I, Sijbrands E, Walter J, Hendriks J, Groen A, Staels B, Lütjohann D, Vanmierlo T, and Mulder M
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Aniline Compounds pharmacology, Animals, Astrocytes cytology, Astrocytes drug effects, Astrocytes metabolism, Cognition drug effects, Cognition physiology, Culture Media, Conditioned pharmacology, Disease Models, Animal, Gene Expression Regulation, Genes, Reporter, Hippocampus drug effects, Hippocampus metabolism, Hippocampus pathology, Humans, Liver X Receptors agonists, Liver X Receptors metabolism, Luciferases genetics, Luciferases metabolism, Male, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Mice, Transgenic, Microglia cytology, Microglia drug effects, Microglia metabolism, Neuroprotective Agents isolation & purification, Peptide Fragments antagonists & inhibitors, Peptide Fragments metabolism, Plaque, Amyloid genetics, Plaque, Amyloid metabolism, Plaque, Amyloid physiopathology, Signal Transduction, Stigmasterol isolation & purification, Stigmasterol pharmacology, Thiazoles pharmacology, Alzheimer Disease drug therapy, Amyloid beta-Peptides genetics, Liver X Receptors genetics, Neuroprotective Agents pharmacology, Peptide Fragments genetics, Plaque, Amyloid drug therapy, Sargassum chemistry, Stigmasterol analogs & derivatives
- Abstract
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 LXRβ. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal Aβ 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 LXRα 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 Aβ
42 . Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of Aβ. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXRβ activation.- Published
- 2019
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