Nikita Martens 1,2,*, Melissa Schepers 2,3,*, Na Zhan 1,4, Frank Leijten 1, Gardi Voortman 1, Assia Tiane 2,3, Ben Rombaut 2,3, Janne Poisquet 2, Nienke van de Sande 1,3, Anja Kerksiek 5, Folkert Kuipers 6, Johan W. Jonker 6, Hongbing Liu 4, Dieter Lütjohann5,*, Tim Vanmierlo1,2,3,* and Monique T. Mulder1,*.
1Department of Internal Medicine, Section Pharmacology and Vascular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; 2Department of Neuroscience, Biomedical Research Institute, Hasselt University, European Graduate School of Neuroscience, Hasselt, Belgium; 3Department of Psychiatry and Neuropsychology, School for Mental Health and Neurosciences, Division Translational Neuroscience, Maastricht University, Maastricht, The Netherlands; 4Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China; 5Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; 6Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, Groningen, The Netherlands.
*Equally contributed
Accumulating evidence indicates a key role for a disturbed cerebral cholesterol transport in the development and progression of Alzheimer’s Disease (AD). We showed that memory of AD mice improves upon activation of brain cholesterol turnover by synthetic activators of liver X receptors (LXRα/β). However, serious side effects including hepatic steatosis render these LXRα/β activators unsuitable for patients. We found that the seaweed Sargassum fusiforme, containing preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced Aβ deposition in an AD mouse model without inducing hepatic steatosis. However, Sargassum fusiforme also contains relatively high amounts of toxic elements such as inorganic arsenic (iAs), hampering the translation to humans. The use of a pure compound could serve as an alternative. We examined the effects of purified 24(S)-saringosterol on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wild-type 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) via oral gavage for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by qPCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. 24(S)-Saringosterol prevented the increase in inflammatory marker Iba1 in the hippocampus and cortex of APPswePS1ΔE9 mice. 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 Aβ 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. Currently, we are investigating the potential of a Sargassum fusiforme extract free of heavy metals generated by supercritical fluid extraction and other seaweed species containing limited amounts of these toxic elements.