AP-2β regulates amyloid beta-protein stimulation of apolipoprotein E transcription in astrocytes.
Two key players involved in Alzheimer's disease (AD) are amyloid beta protein (Aβ) and apolipoprotein E (apoE). Aβ increases apoE protein levels in astrocytes which is associated with cholesterol trafficking, neuroinflammatory responses and Aβ clearance. The mechanism for the increase in apoE protein abundance is not understood. Based on different lines of evidence, we propose that the beta-adrenergic receptor (βAR), cAMP and the transcription factor activator protein-2 (AP-2) are contributors to the Aβ-induced increase in apoE abundance. This hypothesis was tested in mouse primary astrocytes and in cells transfected with an apoE promoter fragment with binding sites for AP-2. Aβ(42) induced a time-dependent increase in apoE mRNA and protein levels which were significantly inhibited by βAR antagonists. A novel finding was that Aβ incubation significantly reduced AP-2α levels and significantly increased AP-2β levels in the nuclear fraction. The impact of Aβ-induced translocation of AP-2 into the nucleus was demonstrated in cells expressing AP-2 and incubated with Aβ(42). AP-2 expressing cells had enhanced activation of the apoE promoter region containing AP-2 binding sites in contrast to AP-2 deficient cells. The transcriptional upregulation of apoE expression by Aβ(42) may be a neuroprotective response to Aβ-induced cytotoxicity, consistent with apoE's role in cytoprotection.
Department of Pharmacology, University of Minnesota School of Medicine, Geriatric Research Education and Clinical Center, VAMC, Minneapolis, MN 55455, USA.
Ximena S
XS
Rossello
Urule
U
Igbavboa
Gary A
GA
Weisman
Grace Y
GY
Sun
W Gibson
WG
Wood
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D050656:Transcription Factor AP-2 / Q000378:metabolism / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D050656:Transcription Factor AP-2; C075222:amyloid beta-protein (1-42)