Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model

Nikita Martens^{1

2}, Na Zhan^{1

3

4}, Sammie C Yam¹, Marcella Palumbo⁵, Lorenzo Pontini⁶, Frank P J Leijten¹, Leonie van Vark-van der Zee¹, Gardi Voortman¹, Silvia Friedrichs⁴, Albert Gerding⁷, Maura Marinozzi⁶, Johan W Jonker⁷, Folkert Kuipers^{7

8}, Dieter Lütjohann⁴, Tim Vanmierlo^{1

2

9}, Monique T Mulder¹

Affiliations

¹ Department of Internal Medicine, Section Pharmacology and Vascular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.
³ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
⁴ Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
⁵ Department of Food and Drug, University of Parma, Parma, Italy.
⁶ Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
⁷ Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁸ European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹ Department Psychiatry and Neuropsychology, Mental Health and Neuroscience Institute, Maastricht University, Maastricht, The Netherlands.

PMID: 40233928
DOI: 10.1111/bph.70031

Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model

Nikita Martens et al. Br J Pharmacol. 2025 Aug.

. 2025 Aug;182(16):3744-3766.

doi: 10.1111/bph.70031. Epub 2025 Apr 15.

Authors

Affiliations

¹ Department of Internal Medicine, Section Pharmacology and Vascular Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.
³ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
⁴ Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
⁵ Department of Food and Drug, University of Parma, Parma, Italy.
⁶ Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
⁷ Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁸ European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹ Department Psychiatry and Neuropsychology, Mental Health and Neuroscience Institute, Maastricht University, Maastricht, The Netherlands.

PMID: 40233928
DOI: 10.1111/bph.70031

Abstract

Background and purpose: Liver X receptors (LXRs) are promising therapeutic targets for alleviating Alzheimer's disease (AD) symptoms. We assessed the impact of the semi-synthetic LXR agonist 22-ketositosterol on disease progression in an AD mouse model.

Experimental approach: From 5.5 months of age, APPswePS1ΔE9 (AD) mice and wild-type (WT) littermates received a regular or 22-ketositosterol-supplemented diet (0.017% w/w). Cognition was assessed with object location and recognition tasks and a spontaneous alternation Y-maze test. Amyloid β was quantified using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), microglia (Iba1, CD68) and astrocyte (GFAP) markers using IHC. Sterols were determined in food, serum, liver and cerebellum.

Key results: 22-Ketositosterol activated both liver X receptors-α and -β and promoted cholesterol efflux in cell cultures. Diet supplementation with 22-ketositosterol prevented a decline in the performance of APPswePS1ΔE9 mice in the object location task but not in the other two tasks. Without affecting amyloid β deposition, 22-ketositosterol decreased microglia (Iba1, CD68) and astrocyte (GFAP) markers in the cortex and hippocampus of APPswePS1ΔE9, suggesting potential anti-inflammatory effects. No lipid accumulation was detected in the liver or serum upon 22-ketositosterol supplementation.

Conclusions and implications: Diet supplementation with 22-ketositosterol prevented the decline in spatial memory of APPswePS1ΔE9 mice. Our data suggest therapeutic benefits of 22-ketositosterol possibly by enhancing cholesterol efflux and mitigating inflammatory responses, without inducing hepatosteatosis or hypertriglyceridemia.

Keywords: Alzheimer's disease; cholesterol metabolism; liver X receptors; oxysterols.

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References

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Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model

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Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model

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