1. Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model
- Author
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Dicky Struik, Niels Hellings, Anja Kerksiek, Melissa Schepers, Ilse Dewachter, Frank P.J. Leijten, Johan W. Jonker, Yupyn Chintapakorn, Thiti Suttiyut, Monique T. Mulder, Hong-Bing Liu, Tim Vanmierlo, Eric J.G. Sijbrands, Jochen Walter, Surachai Pornpakakul, Jeroen F. J. Bogie, Dieter Lütjohann, Assia Tiane, Bart Staels, Ann Cuypers, Albert K. Groen, Jerome J. A. Hendriks, Cindy Hoeks, Pilar Martinez-Martinez, Experimental Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Promovendi MHN, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Internal Medicine, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)
- Subjects
0301 basic medicine ,Male ,lcsh:Medicine ,Plaque, Amyloid ,Pharmacology ,Hippocampus ,ACTIVATION ,chemistry.chemical_compound ,0302 clinical medicine ,Cognition ,Genes, Reporter ,Lipid droplet ,BRAIN ,lcsh:Science ,Luciferases ,Liver X Receptors ,Multidisciplinary ,beta-Sitosterol ,Aniline Compounds ,Microglia ,Chemistry ,LIVER-X RECEPTORS ,BETA-SITOSTEROL ,LXR AGONIST TO901317 ,3. Good health ,medicine.anatomical_structure ,Memory, Short-Term ,Neuroprotective Agents ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Signal Transduction ,Stigmasterol ,Mice, Transgenic ,HUMAN SERUM-ALBUMIN ,METABOLISM ,Article ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Animals ,Humans ,Liver X receptor ,Amyloid beta-Peptides ,PLANT STEROLS ,Activator (genetics) ,lcsh:R ,Hypertriglyceridemia ,Sargassum ,medicine.disease ,Peptide Fragments ,Disease Models, Animal ,Thiazoles ,MICE ,030104 developmental biology ,Gene Expression Regulation ,CHOLESTEROL HOMEOSTASIS ,Astrocytes ,Culture Media, Conditioned ,lcsh:Q ,Steatosis ,030217 neurology & neurosurgery - 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 Aβ42. 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. This work was supported by the Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Nederland (AN), Scientific Research-Flanders (FWO), Fondation Vaincre Alzheimer (LECMA), and Alzheimer Forschung Initiative (AFI). The authors like to thank Joke Vanhoof for excellent technical assistance and AstraZeneca for providing the AZ876 compound through the AstraZeneca Open Innovation program. We sincerely thank Patric Delhanty for editing the paper and Kenneth Vanbrabant for performing the GC-MS analysis.
- Published
- 2019