期刊
NEUROBIOLOGY OF AGING
卷 30, 期 12, 页码 2010-2020出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2008.02.015
关键词
Aging; Alzheimer's disease; Egr-1; Hipk2; IGF1-R; p75(NTR); TrkA
资金
- P.H.S.
- University of Verona, Italy
The aging program mediated by IGF1-R is responsible for a naturally occumng TrkA to p75(NT)R switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid beta-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75(NTR), or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA to p75(NTR) switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75(NTR), whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75(NTR), whereas similar approaches directed against Hipk-2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75(NTR) and TrkA, respectively Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p,44 transgene in p44(+/+) animals, a model of accelerated aging, (C) 2008 Elsevier Inc All rights reserved.
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