Department of Psychiatry, Vanderbilt University, Nashville, TN37232, USA.
Mol Neurodegener. 2008 Oct 3;3:14. doi: 10.1186/1750-1326-3-14.
Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes.
To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2-8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts.
The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/gamma-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.
早老素（PSEN1 和 PSEN2）家族性阿尔茨海默病相关变体通过功能获得和功能丧失机制促进疾病的病理生理学。在小鼠前脑中缺失 PSEN1 和 PSEN2 会导致强烈而进行性的神经退行性表型，其特征是解剖和行为改变。
为了更好地了解与这些形态和行为表型相关的分子变化，我们对 PSEN1/PSEN2 双敲除小鼠及其同窝对照的海马体和前额叶皮层进行了 DNA 微阵列转录组谱分析，年龄范围从 2 到 8 个月不等。我们的数据表明，PSEN1 和 PSEN2 的联合缺乏导致与神经退行性变和神经炎症相关的进行性、年龄依赖性转录组特征。虽然这些事件在海马体和前额叶皮层中的进展可能不同，但最关键的表达特征在两个脑区都很常见，涉及组织蛋白酶和补体系统转录物的强烈上调。
观察到的神经炎症表达变化可能与 PSEN1 和 PSEN2 复合缺失小鼠中观察到的神经退行性表型有因果关系。此外，我们的结果表明，评估 PS/g 分泌酶活性抑制剂治疗阿尔茨海默病时，必须密切监测钙蛋白酶-组织蛋白酶系统激活的迹象。
