Nikita Martens 1,2,*, Na Zhan 1,4, Melissa Schepers 2,3,*, Frank Leijten 1, Gardi Voortman 1, Ben Rombaut 2,3, 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, Division 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.
Supported by NWO-TTW
*Equally contributed
Liver X receptor(LXR)α/β are promising therapeutical targets for treatment of AD as key regulators of both cholesterol homeostasis and inflammatory processes. We found that decline of memory and accumulation of amyloid (A)β in an Alzheimer’s disease (AD) mouse model was prevented by dietary supplementation with the Asian brown seaweed Sargassum fusiforme, containing the LXR-agonist 24(S)-saringosterol. No adverse effects, such as hepatic steatosis, were observed. We examined if Himanthalia (H.) elongata harvested from the North Sea, containing similar concentrations of 24(S)-saringosterol as S. fusiforme, could prevent development of cognitive decline and neuropathology in AD mice. First, we demonstrated LXR-activating capacities of H. elongata lipophilic extracts using a Luciferase assay. Accordingly, expression of LXR-target genes was upregulated by H. elongata extracts in several cell lines. Subsequently, we assessed the effects of administration of H. elongata based on its 24(S)-saringosterol content (0.5 mg/25 g body weight/day) for 10 weeks to six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates on cognition assessed by object recognition and location tasks: H. elongata administration prevented cognitive decline in APPswePS1ΔE9 mice. Presently we are assessing the effects of treatment on neuropathology, including a.o. Aβ plaque load, inflammatory markers, and synaptic density and on cholesterol turnover. Potential adverse effects will be assessed by determining hepatic neutral lipid content and gene expression patterns. In conclusion, H. elongata administration prevented cognitive decline in APPswePS1ΔE9 mice and, although effects on neuropathology remain to be determined, appears to be promising for prevention or treatment of features of AD.