Costantini Claudio, Scrable Heidi, Puglielli Luigi
Department of Medicine, University of Wisconsin-Madison, Veterans Administration Hospital (GRECC 11G), 53705, USA.
EMBO J. 2006 May 3;25(9):1997-2006. doi: 10.1038/sj.emboj.7601062. Epub 2006 Apr 13.
Aging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75(NTR). An expression pattern in which TrkA predominates in younger animals switches to one in which p75(NTR) predominates in older animals. This TrkA-to-p75(NTR) switch is accompanied by activation of the second messenger ceramide, stabilization of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid beta-peptide (Abeta). Here, we show that the insulin-like growth factor-1 receptor (IGF1-R), the common regulator of lifespan and age-related events in many different organisms, is responsible for the TrkA-to-p75(NTR) switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75(NTR) downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53. We also show that hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of aging, is characterized by early TrkA-to-p75(NTR) switch and increased production of Abeta in the brain.
大脑衰老的特征是神经营养因子受体TrkA和p75（NTR）的表达水平发生显著变化。在年幼动物中以TrkA占主导的表达模式，在年老动物中转变为p75（NTR）占主导的模式。这种从TrkA到p75（NTR）的转变伴随着第二信使神经酰胺的激活、β-位点淀粉样前体蛋白裂解酶-1（BACE1）的稳定以及淀粉样β肽（Aβ）生成的增加。在此，我们表明胰岛素样生长因子-1受体（IGF1-R），作为许多不同生物体寿命和与年龄相关事件的共同调节因子，在人类神经母细胞瘤细胞系和小鼠脑原代神经元中均负责从TrkA到p75（NTR）的转变。在IGF1-R下游控制TrkA和p75（NTR）水平的信号通路需要IRS2、PIP3/Akt，并且受PTEN和p44（p53的短异构体）的控制。我们还表明，在表现出加速衰老形式的p44转基因动物中，IGF1-R信号的过度激活的特征是大脑中早期从TrkA到p75（NTR）的转变以及Aβ生成的增加。
