Clement A B, Hanstein R, Schröder A, Nagel H, Endres K, Fahrenholz F, Behl C
Department of Pathobiochemistry, Johannes Gutenberg-University, Medical School, Duesbergweg 6, 55099 Mainz, Germany.
Neuroscience. 2008 Mar 18;152(2):459-68. doi: 10.1016/j.neuroscience.2007.10.060. Epub 2008 Jan 12.
A disintegrin and metalloprotease (ADAM) 10 is the main candidate enzyme for the alpha-secretase processing of the amyloid precursor protein (APP). Neuron-specific ADAM10 overexpression proved beneficial in the APP[V717I] mutant Alzheimer mouse model [Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456-1464]. Since Alzheimer patients have a high prevalence for epileptic seizures, we investigated the effects of ADAM10 modulation under conditions of experimentally induced epileptic seizures. In this context we also examined whether ADAM10 effects were influenced by APP levels. Therefore we compared severity of kainate-induced seizures, neurodegeneration and inflammation in double transgenic mice overexpressing functional ADAM10 or a dominant negative ADAM10 mutant in the APP[V717I] background with single transgenic ADAM10 modulated mice. Double transgenic dominant negative ADAM10dn/APP[V717I] mice suffered from stronger epileptic seizures, had a longer recovery period and showed more neurodegeneration and glial activation in the hippocampal region than double transgenic mice moderately overexpressing functional ADAM10 (ADAM10mo/APP[V717I]) and APP[V717I] mice with endogenous ADAM10 levels. This suggests that ADAM10 activity is necessary to provide neuroprotection against excitotoxicity in the APP[V717I] mouse model. Interestingly, increased expression of functional ADAM10 above the endogenous level did not correlate with a better protection against seizures and neurodegeneration. Furthermore, ADAM10 dominant negative mice without transgenic APP overexpression (ADAM10dn) were seizing for a shorter time and showed less neuronal cell death and neuroinflammation after kainate injection than wild-type mice, which shows beneficial effects of ADAM10 inhibition in context with neurodegeneration. In contrast, mice with a high ADAM10 overexpression showed more seizures and stronger neuronal damage and inflammation than wild-type mice and mice with moderate ADAM10 overexpression. Hence, additional cleavage products of ADAM10 may counterbalance the neuroprotective effect of alpha-secretase-cleaved APP in the defense against excitotoxicity. Our findings highlight the need of a careful modulation of ADAM10 activity for neuroprotection depending on substrate availability and on neurotoxic stress conditions.
解整合素金属蛋白酶（ADAM）10是淀粉样前体蛋白（APP）α-分泌酶切割过程的主要候选酶。在APP[V717I]突变的阿尔茨海默病小鼠模型中，神经元特异性ADAM10过表达已被证明有益[波斯蒂纳R，施罗德A，德瓦赫特I，博尔J，施密特U，科伊罗E，普林曾C，恩德斯K，希姆克C，布莱辛M，弗拉梅兹P，德凯纳A，戈多克斯E，范勒文F，法伦霍尔茨F（2004年）一种解整合素金属蛋白酶可预防阿尔茨海默病小鼠模型中的淀粉样斑块形成和海马缺陷。《临床研究杂志》113：1456 - 1464]。由于阿尔茨海默病患者癫痫发作的患病率很高，我们研究了在实验性诱导癫痫发作的条件下ADAM10调节的作用。在此背景下，我们还研究了ADAM10的作用是否受APP水平的影响。因此，我们比较了在APP[V717I]背景下过表达功能性ADAM10或显性负性ADAM10突变体的双转基因小鼠与单转基因ADAM10调节小鼠中，海藻酸诱导的癫痫发作严重程度、神经退行性变和炎症情况。与适度过表达功能性ADAM10的双转基因小鼠（ADAM10mo/APP[V717I]）和内源性ADAM10水平的APP[V717I]小鼠相比，双转基因显性负性ADAM10dn/APP[V717I]小鼠癫痫发作更强，恢复期更长，海马区神经退行性变和胶质细胞活化更明显。这表明在APP[V717I]小鼠模型中，ADAM10活性对于提供针对兴奋性毒性的神经保护是必要 的。有趣的是，功能性ADAM10表达增加至高于内源性水平与更好地预防癫痫发作和神经退行性变并无关联。此外，未过表达转基因APP的ADAM10显性负性小鼠（ADAM10dn）注射海藻酸后癫痫发作时间更短，神经元细胞死亡和神经炎症比野生型小鼠更少，这表明在神经退行性变方面ADAM10抑制具有有益作用。相比之下，ADAM10过表达高的小鼠比野生型小鼠以及ADAM10适度过表达的小鼠癫痫发作更多，神经元损伤和炎症更强。因此，ADAM10的其他切割产物可能会在抵御兴奋性毒性方面抵消α-分泌酶切割的APP 的神经保护作用。我们的研究结果强调，根据底物可用性和神经毒性应激条件，谨慎调节ADAM10活性对于神经保护是必要的。
