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24-Hydroxycholesterol Moderates the Effects of Amyloid-beta on Expression of HMG-CoA Reductase and ABCA1 Proteins in Mouse Astrocytes

Advanced biomedical research(2023)

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Abstract
Background: Elevated brain cholesterol increases the risk of Alzheimer's disease. Production of 24-hydroxycholesterol (24s-OHC) by neurons prevents cholesterol accumulation in the brain. In this study, we investigated the effect of 24s-OHC on the HMG-COA reductase and ABCA1 which are involved in the brain cholesterol homeostasis with or without beta-amyloid in astrocytes. Methods and Materials: Astrocytes were treated with 24s-OHC with or without A beta. Western blot and real-time polymerase chain reaction were done to detect protein and gene expression of beta-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and ABCA1, respectively. Cholesterol release was determined using a quantitation kit. Results: Protein levels of HMGCR and ABCA1 were significantly increased by A beta; however, the 24s-OHC was able to restore their levels and diminish the effect of amyloid-beta. A beta did not have a significant effect on HMGCR expression, while 24s-OHC reduced it by 68%. A beta-induced ABCA1 expression did not increase cholesterol efflux as the lower levels of cholesterol in conditioned medium of A beta-treated cells were found. Conclusion: Our novel findings show that A beta affects two key elements in the brain cholesterol homeostasis, HMGCR and ABCA1, which are crucial in cholesterol synthesis and efflux. Since 24s-OHC could suppress the A beta effects on enhancement of HMGCR and ABCA1, therefore the cytochrome P450 46A1 (Cyp46A1), which is exclusively expressed in the central nervous system and responsible for producing of 24s-OHC, could consider as a therapeutic target in the cholesterol-related neurodegenerative diseases such as Alzheimer's disease.
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Key words
ABCA1, amyloid beta-peptides, brain, cholesterol, hydroxycholesterols, HMG-CoA
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