Van Nostrand William E, Melchor Jerry P, Romanov Galina, Zeigler Kelly, Davis Judianne
Departments of Medicine and Pathology, HSC T-15/081, Health Sciences Center, State University of New York, Stony Brook, NY 11794-8153, USA.
Ann N Y Acad Sci. 2002 Nov;977:258-65. doi: 10.1111/j.1749-6632.2002.tb04824.x.
Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Abeta region of the Abeta protein precursor (AbetaPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Abeta region (D23N) of AbetaPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant Abeta40 peptides rapidly assemble in solution to form fibrils compared to wild-type Abeta40. Similarly, the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell-associated AbetaPP, proteolytic breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa Abeta40 was more potent than either single-mutant form of Abeta in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Abeta towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Abeta peptide further enhances the fibrillogenic and pathogenic properties of Abeta. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AbetaPP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double-mutant E22Q/D23N Dutch/Iowa AbetaPP leads to robust deposition of Abeta in a vascular-weighted manner.
脑淀粉样β蛋白血管病（CAA）是阿尔茨海默病及某些相关疾病患者的关键病理特征。已在β淀粉样蛋白前体（AβPP）基因的Aβ区域内鉴定出几种突变，这些突变似乎会加重CAA的严重程度。在AβPP的Aβ区域（D23N）内鉴定出一种新突变，该突变与爱荷华州一个家族中的严重CAA相关。最近，我们发现，与野生型Aβ40相比，E22Q荷兰突变体、D23N爱荷华突变体以及E22Q/D23N荷兰/爱荷华双突变体Aβ40肽在溶液中能迅速组装形成纤维。同样，发现E22Q荷兰突变体和D23N爱荷华突变体Aβ40肽能在培养的人脑血管平滑肌（HCSM）细胞中引发强烈的病理反应，包括细胞相关AβPP水平升高、肌动蛋白的蛋白水解降解以及细胞死亡。双突变体E22Q/D23N荷兰/爱荷华Aβ40在HCSM细胞中引发病理反应方面比任何一种单突变体Aβ都更有效。这些体外数据表明，E22Q荷兰突变和D23N爱荷华突变促进了Aβ的纤维形成以及对HCSM细胞的致病性。此外，同一Aβ肽中同时存在这两种CAA突变会进一步增强Aβ的纤维形成和致病特性。我们还构建了转基因小鼠模型，以研究AβPP中单个和双重CAA突变在体内的影响。对转基因小鼠大脑的初步分析表明，双突变体E22Q/D23N荷兰/爱荷华AβPP的表达会导致Aβ以血管加权的方式大量沉积。
