Westmark Cara J, Westmark Pamela R, Malter James S
Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI 53705, USA.
Int J Clin Exp Pathol. 2009 Oct 10;3(1):56-68.
Metabotropic glutamate receptor 5 (mGluR(5)) regulates the translation of amyloid precursor protein (APP) mRNA. Under resting conditions, mRNA is bound to and translationally repressed by the fragile X mental retardation protein (FMRP). Upon group 1 mGluR activation, FMRP dissociates from the mRNA and translation ensues. APP levels are elevated in the dendrites of primary neuronal cultures as well as in synaptoneurosomes (SN) prepared from embryonic and juvenile fmr-1 knockout (KO) mice, respectively. In order to study the effects of APP and its proteolytic product Abeta on Fragile X syndrome (FXS) phenotypes, we created a novel mouse model (FRAXAD) that over-expresses human APPSwe/Abeta in an fmr-1 KO background. Herein, we assess (1) human APP(Swe) and Abeta levels as a function of age in FRAXAD mice, and (2) seizure susceptibility to pentylenetetrazol (PTZ) after mGluR(5) blockade. PTZ-induced seizure severity is decreased in FRAXAD mice pre-treated with the mGluR(5) antagonist MPEP. These data suggest that Abeta contributes to seizure incidence and may be an appropriate therapeutic target to lessen seizure pathology in FXS, Alzheimer's disease (AD) and Down syndrome (DS) patients.
代谢型谷氨酸受体5（mGluR(5)）调节淀粉样前体蛋白（APP）mRNA的翻译。在静息状态下，mRNA与脆性X智力低下蛋白（FMRP）结合并受到翻译抑制。在第1组mGluR激活后，FMRP从mRNA上解离，随后发生翻译。在原代神经元培养物的树突以及分别从胚胎和幼年fmr-1基因敲除（KO）小鼠制备的突触体（SN）中，APP水平均升高。为了研究APP及其蛋白水解产物β淀粉样蛋白（Aβ）对脆性X综合征（FXS）表型的影响，我们创建了一种新型小鼠模型（FRAXAD），该模型在fmr-1基因敲除背景下过表达人APP Swe/Aβ。在此，我们评估（1）FRAXAD小鼠中人类APP(Swe)和Aβ水平随年龄的变化，以及（2）mGluR(5)阻断后对戊四氮（PTZ）的癫痫易感性。用mGluR(5)拮抗剂MPEP预处理的FRAXAD小鼠中，PTZ诱导的癫痫严重程度降低。这些数据表明，Aβ促成癫痫发作，可能是减轻FXS、阿尔茨海默病（AD）和唐氏综合征（DS）患者癫痫病理的合适治疗靶点。
