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

Overview

Journal Adv Biomed Res

Specialty Biomedical Engineering

Date 2023 Aug 11

PMID 37564436

Authors

Zahra Nazeri

Ghorban Mohammadzadeh

Mojtaba Rashidi

Shirin Azizdoost

Maryam Cheraghzadeh

Alireza Kheirollah

Affiliations

Soon will be listed here.

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 β-amyloid in astrocytes.

Methods And Materials: Astrocytes were treated with 24s-OHC with or without Aβ. Western blot and real-time polymerase chain reaction were done to detect protein and gene expression of β-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 Aβ; however, the 24s-OHC was able to restore their levels and diminish the effect of amyloid-β. Aβ did not have a significant effect on HMGCR expression, while 24s-OHC reduced it by 68%. Aβ-induced ABCA1 expression did not increase cholesterol efflux as the lower levels of cholesterol in conditioned medium of Aβ-treated cells were found.

Conclusion: Our novel findings show that Aβ 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 Aβ 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.

Citing Articles

A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3.

Valencia-Olvera A, Balu D, Bellur S, McNally T, Saleh Y, Pham D Alzheimers Res Ther. 2023; 15(1):216.

PMID: 38102668 PMC: 10722727. DOI: 10.1186/s13195-023-01353-z.

References

Ho W, Hartmann H, Ling S . Central nervous system cholesterol metabolism in health and disease. IUBMB Life. 2022; 74(8):826-841. DOI: 10.1002/iub.2662. View

Mast N, Verwilst P, Wilkey C, Guengerich F, Pikuleva I . In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds. J Med Chem. 2019; 63(12):6477-6488. PMC: 7226586. DOI: 10.1021/acs.jmedchem.9b01383. View

Feng W, Zhang Y, Wang Z, Xu H, Wu T, Marshall C . Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer's disease mouse model with suppression of glymphatic clearance. Alzheimers Res Ther. 2020; 12(1):125. PMC: 7532614. DOI: 10.1186/s13195-020-00688-1. View

Azizidoost S, Babaahmadi-Rezaei H, Nazeri Z, Cheraghzadeh M, Kheirollah A . Amyloid beta increases ABCA1 and HMGCR protein expression, and cholesterol synthesis and accumulation in mice neurons and astrocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2021; 1867(1):159069. DOI: 10.1016/j.bbalip.2021.159069. View

DeBose-Boyd R . Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res. 2008; 18(6):609-21. PMC: 2742364. DOI: 10.1038/cr.2008.61. View

Rodriguez-Rodriguez E, Mateo I, Infante J, Llorca J, Garcia-Gorostiaga I, Vazquez-Higuera J . Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk. Brain Res. 2009; 1280:166-71. DOI: 10.1016/j.brainres.2009.05.019. View

Mast N, Lin J, Anderson K, Bjorkhem I, Pikuleva I . Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1). PLoS One. 2017; 12(10):e0187168. PMC: 5658173. DOI: 10.1371/journal.pone.0187168. View

Matsuo M . ABCA1 and ABCG1 as potential therapeutic targets for the prevention of atherosclerosis. J Pharmacol Sci. 2022; 148(2):197-203. DOI: 10.1016/j.jphs.2021.11.005. View

Azizidoost S, Babaahmadi-Rezaei H, Nazeri Z, Cheraghzadeh M, Kheirollah A . Impact of Methyl-β-Cyclodextrin and Apolipoprotein A-I on The Expression of ATP-Binding Cassette Transporter A1 and Cholesterol Depletion in C57BL/6 Mice Astrocytes. Cell J. 2021; 23(1):93-98. PMC: 7944131. DOI: 10.22074/cellj.2021.7061. View

10.

Samant N, Gupta G . Novel therapeutic strategies for Alzheimer's disease targeting brain cholesterol homeostasis. Eur J Neurosci. 2020; 53(2):673-686. DOI: 10.1111/ejn.14949. View

11.

Eskandari M, Mellati A . Liver X Receptor as a Possible Drug Target for Blood-Brain Barrier Integrity. Adv Pharm Bull. 2022; 12(3):466-475. PMC: 9348539. DOI: 10.34172/apb.2022.050. View

12.

Adorni M, Cipollari E, Favari E, Zanotti I, Zimetti F, Corsini A . Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis. 2016; 256:1-6. DOI: 10.1016/j.atherosclerosis.2016.11.019. View

13.

Gamba P, Giannelli S, Staurenghi E, Testa G, Sottero B, Biasi F . The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer's Disease. Antioxidants (Basel). 2021; 10(5). PMC: 8151638. DOI: 10.3390/antiox10050740. View

14.

Gliozzi M, Musolino V, Bosco F, Scicchitano M, Scarano F, Nucera S . Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues. Pharmacol Res. 2020; 163:105215. DOI: 10.1016/j.phrs.2020.105215. View

15.

Chen Y, Qin C, Huang J, Tang X, Liu C, Huang K . The role of astrocytes in oxidative stress of central nervous system: A mixed blessing. Cell Prolif. 2020; 53(3):e12781. PMC: 7106951. DOI: 10.1111/cpr.12781. View

16.

Muse E, Yu S, Edillor C, Tao J, Spann N, Troutman T . Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. Proc Natl Acad Sci U S A. 2018; 115(20):E4680-E4689. PMC: 5960280. DOI: 10.1073/pnas.1714518115. View

17.

Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S . Alterations in cholesterol metabolism as a risk factor for developing Alzheimer's disease: Potential novel targets for treatment. J Steroid Biochem Mol Biol. 2019; 190:104-114. DOI: 10.1016/j.jsbmb.2019.03.003. View

18.

Jin U, Park S, Park S . Cholesterol Metabolism in the Brain and Its Association with Parkinson's Disease. Exp Neurobiol. 2019; 28(5):554-567. PMC: 6844833. DOI: 10.5607/en.2019.28.5.554. View

19.

Petrov A, Lam M, Mast N, Moon J, Li Y, Maxfield E . CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice. Neurotherapeutics. 2019; 16(3):710-724. PMC: 6694340. DOI: 10.1007/s13311-019-00737-0. View

20.

Cao J, Zhong M, Toro C, Zhang L, Cai D . Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis. Neurosci Lett. 2019; 703:68-78. PMC: 6760990. DOI: 10.1016/j.neulet.2019.03.016. View