Jeroen Bogie 1, Cindy Hoeks 1, Melissa Schepers 1,2, Assia Tiane 1,2Ann Cuypers 3, Frank Leijten 4, Yupyn Chintapakorn 5, Thiti Suttiyut 5, Surachai Pornpakakul 6, Dicky Struik 7, Anja Kerksiek 8, Hong-Bing Liu 9, Niels Hellings 1, Pilar Martinez-Martinez 2, Johan W Jonker 7, Ilse Dewachter 1, Eric Sijbrands 4, Jochen Walter 10, Jerome Hendriks 1, Albert Groen 11, Bart Staels 12, Dieter Lütjohann 8, , Monique Mulder 4*, Tim Vanmierlo 13, 14*
1Department of Immunology and Biochemistry, Biomedical research institute, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium.
2School for mental health and neuroscience, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
3Centre for Environmental Sciences, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium.
4Department of Internal Medicine, Laboratory of Vascular Medicine, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
5Center of Excellence in Environment and Plant Physiology, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
6Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
7Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
8Institute for Clinical Chemistry and Clinical Pharmacology, Sigmund-Freud-Str. 25, D-53127, Bonn, Germany.
9Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Yushan Road 5, 266003, Qingdao, China.
10Department of Neurology, Molecular Cell Biology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
11Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
12University of Lille – EGID, Inserm, U1011, University Hospital CHU, Institut Pasteur de Lille, F-59019, Lille, France.
13Department of Immunology and Biochemistry, Biomedical research institute, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium. tim.vanmierlo@uhasselt.be.
14School for mental health and neuroscience, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands. tim.vanmierlo@uhasselt.be.
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.