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.
University of Minnesota Ph.D. dissertation. September 2009. Major: Pharmacology. Advisor: W. Gibson Wood. 1 computer file (PDF); viii, 112 pages.
Rossello, Ximena Serenella.
AB affects apoE transcriptionally through the activation of B-AR, cAMP and AP-2.
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