AB affects apoE transcriptionally through the activation of B-AR, cAMP and AP-2

Abstract

Two key players in the development of Alzheimer’s disease (AD) are amyloid beta protein (Aβ) and apolipoprotein E (apoE). We and others have reported that Aβ elevates apoE protein levels in astrocytes, which in turn could alter lipid trafficking and cell function. The mechanism for the Aβ-induced increase in apoE levels is not clearly understood. We propose that Aβ affects apoE transcriptionally through the activation of the beta-adrenergic receptor (βAR), cAMP and the activator protein 2 (AP-2). To test this hypothesis it was first determined if the stimulation of apoE protein levels by Aβ was triggered by an upregulation of apoE mRNA, in contrast to changes in secretion or degradation. The results show a time-dependent increase in apoE mRNA expression levels with peak expression reached after 1 hour of Aβ treatment. βAR antagonists were used to evaluate the involvement of the βAR. The antagonists significantly inhibited the Aβ-induced stimulation of apoE mRNA and protein levels. In order to further understand the mechanism behind these results we assessed cAMP role in the proposed Aβ-apoE pathway. This second messenger has been associated with AD and has been shown to elevate apoE message and secretion levels. The data shows an Aβ-dependent elevation in cAMP levels as well as an increase in apoE levels after dBcAMP treatment, confirming the activation of a cAMP-dependent pathway. In addition, I provide evidence that confirms the participation of the transcription factor AP-2, specifically that of AP-2β. AP-2 is known to be unregulated by cAMP and to bind to the apoE promoter. I report an increase in AP-2β translocation to the nucleus after both cAMP and Aβ treatment and confirm its participation in the activation of the apoE promoter.

In conclusion, my work reveals a novel pathway for Aβ stimulation of apoE abundance in astrocytes involving βAR and the transcription factor AP-2β. These findings not only help clarify the relationship between Aβ and apoE but also help understand AD progression and possibly show a mechanism that could aid in the fight against this fast growing disease.