Du Y, Chen X, Wei X, Bales KR, Berg DT, Paul SM, Farlow MR, Maloney B, Ge YW, Lahiri DK. NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells. Brain Res Mol Brain Res. 2005 May 20;136(1-2):177-88. PubMed.
Recommends
Please login to recommend the paper.
Comments
Washington University
Du and co-workers examine mechanisms of regulation of the ApoE promoter in a human glial cell line by Aβ. ApoE appears likely to play a key role in AD in large part by influencing Aβ metabolism. Thus, understanding the detailed mechanisms of ApoE regulation will provide important insights into AD. It has been previously shown that ApoE is increased in both reactive astrocytes and microglia due to a variety of disease states, including in those cells around AD plaques. Further, it has been shown that Aβ increases levels of the transcription factor NFκβ in cultured cells. This paper demonstrates that there are two NFκβ binding sites in the ApoE promoter, lying within the 1,054 base pairs 5’ to the transcriptional start site. Further, it is nicely shown, through mutational analysis, that the distal NFκβ site appears to be responsible for the Aβ-induced increase in ApoE. The Aβ-induced increase in ApoE is blocked by salicylate, an NFκβ inhibitor. From a practical standpoint, this and previous studies suggest that modulators of NFκβ in glial cells, such as Aβ and cytokines, and the blockade of their effects by compounds like nonsteroidal anti-inflammatories (NSAIDs) will impact ApoE levels in the CNS. Further studies to determine whether the same findings are seen in vivo will also be important. Whether increasing or decreasing human ApoE levels is a “positive” or “negative” modulator of Aβ deposition and toxicity still needs to be determined.
Make a Comment
To make a comment you must login or register.