Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model.
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| Natura: | Artículo científico |
| Lingua: | en |
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British journal of pharmacology
2025
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| author | Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T |
| author_facet | Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T |
| collection | PubMed - marine biology |
| contents | Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model. Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T Animals Alzheimer Disease Liver X Receptors Disease Models, Animal Mice Disease Progression Mice, Transgenic Male Stigmasterol Cholesterol Amyloid beta-Peptides Mice, Inbred C57BL Microglia 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. 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. 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. 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. |
| format | Artículo científico |
| id | pubmed_40233928 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | British journal of pharmacology |
| record_format | pubmed |
| spellingShingle | Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model. Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T Animals Alzheimer Disease Liver X Receptors Disease Models, Animal Mice Disease Progression Mice, Transgenic Male Stigmasterol Cholesterol Amyloid beta-Peptides Mice, Inbred C57BL Microglia Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model. Martens, Nikita Zhan, Na Yam, Sammie C Palumbo, Marcella Pontini, Lorenzo Leijten, Frank P J van Vark-van der Zee, Leonie Voortman, Gardi Friedrichs, Silvia Gerding, Albert Marinozzi, Maura Jonker, Johan W Kuipers, Folkert Lütjohann, Dieter Vanmierlo, Tim Mulder, Monique T Animals Alzheimer Disease Liver X Receptors Disease Models, Animal Mice Disease Progression Mice, Transgenic Male Stigmasterol Cholesterol Amyloid beta-Peptides Mice, Inbred C57BL Microglia 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. 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. 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. 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. |
| title | Role for the liver X receptor agonist 22-ketositosterol in preventing disease progression in an Alzheimer's disease mouse model. |
| topic | Animals Alzheimer Disease Liver X Receptors Disease Models, Animal Mice Disease Progression Mice, Transgenic Male Stigmasterol Cholesterol Amyloid beta-Peptides Mice, Inbred C57BL Microglia |
| url | https://pubmed.ncbi.nlm.nih.gov/40233928/ |