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 (Aβ) 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 Aβ. 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 Aβ-pretreated neurons then, HMGCR was assessed. Cholesterol was measured in both cells and media.
Results: Aβ 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 Aβ-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 Aβ. 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 Aβ on ABCA1 which could likely be responsible for altered brain cholesterol metabolism in Alzheimer's disease.
Keywords: Alzheimer's disease; Amyloid-beta; Astrocytes; Brain apoE; Cholesterol; Neuron.
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