Zohar O, Pick C G, Cavallaro S, Chapman J, Katzav A, Milman A, Alkon D L
Blanchette Rockefeller Neurosciences Institute, Johns Hopkins University Academic and Research Building, MD 20850, USA.
Neurobiol Aging. 2005 Aug-Sep;26(8):1167-75. doi: 10.1016/j.neurobiolaging.2004.10.005. Epub 2005 Jan 7.
Plaques found in the brains of patients suffering from Alzheimer's disease (AD) mainly consist of beta-amyloid (Abeta), which is produced by sequential cleaving of amyloid precursor protein (APP) by two proteolytic enzymes, beta- and gamma-secretases. Any change in the fine balance between these enzymes and their substrate may contribute to the etio-pathogenesis of AD. Indeed, the protein level and enzymatic activity of beta-secretase (BACE), but not its mRNA level, were found elevated in brain areas of AD patients who suffer a high load of Abeta plaque formation. Similarly, increased BACE activity but no mRNA change was observed in a transgenic mouse model of AD, tg2576, in which over expression of the Swedish mutated human APP leads to Abeta plaque formation and learning deficits. Based on the recent demonstration of four BACE splice variants with different enzymatic activity, the discrepancy between BACE activity and mRNA expression may be explained by the altered BACE alternative splicing. To test this hypothesis, we studied the expression of all BACE splice variants in different brain areas of tg2576 mice at age of 4 months and 1 year old. We found developmental and regional differences between wild-type and tg2576 mice. Our results indicate that over expression of APP in tg2576 mice leads to the altered alternative splicing of BACE and the increase of its enzymatically more active splice variant (I-501).
在阿尔茨海默病（AD）患者大脑中发现的斑块主要由β-淀粉样蛋白（Aβ）组成，它是由淀粉样前体蛋白（APP）先后被两种蛋白水解酶β-分泌酶和γ-分泌酶切割产生的。这些酶与其底物之间微妙平衡的任何变化都可能导致AD的病因发病机制。事实上，在Aβ斑块形成负荷高的AD患者脑区中，发现β-分泌酶（BACE）的蛋白水平和酶活性升高，但其mRNA水平未升高。同样，在AD转基因小鼠模型tg2576中也观察到BACE活性增加但mRNA无变化，在该模型中，瑞典突变型人类APP的过度表达导致Aβ斑块形成和学习缺陷。基于最近对四种具有不同酶活性的BACE剪接变体的证明，BACE活性与mRNA表达之间的差异可能是由BACE可变剪接改变所解释的。为了验证这一假设，我们研究了4个月和1岁大的tg2576小鼠不同脑区中所有BACE剪接变体的表达。我们发现野生型和tg2576小鼠之间存在发育和区域差异。我们的结果表明，tg2576小鼠中APP的过度表达导致BACE可变剪接改变及其酶活性更高的剪接变体（I-501）增加。
