Amyloid beta increases ABCA1 and HMGCR protein expression, and cholesterol synthesis and accumulation in mice neurons and astrocytes

Introduction: Imbalanced cholesterol metabolism in the brain is one of the main pathophysiological mechanisms involved in Alzheimer's disease. We investigated the effect of amyloid-beta (A beta) on the main proteins involved in regulation of cholesterol metabolism along with cholesterol content in astrocytes and neurons. Methods: Astrocytes and neurons were cultured and treated with A beta. Apolipoprotein E (apoE) level in the cells and conditioned media, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), ATP-binding cassette transporter A1 (ABCA1), and cytochrome P450 46A1 (CYP46A1) in cell lysates were determined using immunoblotting. Astrocyte media was added to the A beta-pretreated neurons then, HMGCR was assessed. Cholesterol was measured in both cells and media. Results: A beta caused a significant increase in HMGCR and ABCA1 protein levels and cholesterol content in both cells without increasing cholesterol efflux. A similar increase was seen for cellular apoE level in astrocytes with no changes in media with a significant reduction of cholesterol efflux. HMGCR level was restored to near control level when A beta-pretreated neurons were exposed to media from culture astrocytes. Conclusion: Almost all events related to cholesterol homeostasis in neurons and astrocytes, are somehow affected by A beta. However, because ABCA1 has the most important role(s) in brain cholesterol homeostasis, all subsequent events associated with astrocytes-cholesterol synthesis and its shuttling to neurons are influenced by the effects of A beta on ABCA1 which could likely be responsible for altered brain cholesterol metabolism in Alzheimer's disease.