THE USE OF SEAWEED-DERIVED PHYTOSTEROLS TO DEFEAT ALZHEIMER'S DISEASE
ATHEROSCLEROSIS(2022)
摘要
Background and Aims : Accumulating evidence indicates a key role for a disturbed cerebral cholesterol transport in the development and progression of 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. We examined the effects of 24(S)-saringosterol on cognition and neuropathology in AD mice.Methods: Six-month-old male APPswePS1ΔE9 mice and wildtype 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.Results: 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.Conclusions: 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. Background and Aims : Accumulating evidence indicates a key role for a disturbed cerebral cholesterol transport in the development and progression of 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. We examined the effects of 24(S)-saringosterol on cognition and neuropathology in AD mice. Methods: Six-month-old male APPswePS1ΔE9 mice and wildtype 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. Results: 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. Conclusions: 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.
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