Charge alterations of E22 enhance the pathogenic properties of the amyloid β-protein
Charge alterations of E22 enhance the pathogenic properties of the amyloid β-protein
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DOI：
10.1046/j.1471-4159.2000.0742209.x
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发表时间：
2000-05-01
影响因子：
4.7
通讯作者：
Van Nostrand, WE
中科院分区：
文献类型：
--
作者：
Melchor, JP;McVoy, L;Van Nostrand, WE
由淀粉样β蛋白（A β）引起的脑淀粉样血管病（CAA）是阿尔茨海默病和荷兰型遗传性脑出血伴淀粉样变性（HCHWA-D）患者的一个关键病理特征。这些疾病中的CAA的特征在于脑血管壁内的平滑肌细胞中A β的沉积。最近，在几个意大利家族中发现了一种新的A β突变E22 K，与HCHWA-D一样，与CAA和出血性卒中相关。这两种类似的疾病，源于A β 22位的氨基酸取代，暗示了该位点在HCHWA病理学中的重要性。先前，我们表明含有E22 Q取代的HCHWA-DA β（1-40）在培养的人脑血管平滑肌细胞（HCSM细胞）中诱导了强烈的病理反应，包括细胞相关A β前体（A β PP）水平的高度升高和细胞死亡。在本研究中，合成了一系列E22突变体A β（1-40）肽，并评估了它们对培养的HCSM细胞的致病特性。定量荧光分析表明，突变A β（1-40）肽或含有电荷损失（E22 Q和E22 A）或电荷变化（E22 K）的HCSM细胞的表面结合，并形成淀粉样纤维。类似地，同一组E22突变A β（1-40）肽在HCSM细胞中引起增强的病理反应。相反，野生型E22或电荷保持E22 DA β（1-40）肽缺乏任何这些致病特性。这些数据表明，A β 22位电荷的改变或丢失增强了肽对HCSM细胞的致病作用，并可能导致表型相关的HCHWA疾病的发病机制。
Cerebral amyloid angiopathy (CAA) due to amyloid beta-protein (A beta) is a key pathological feature of patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D). The CAA in these disorders is characterized by deposition of A beta in the smooth muscle cells within the cerebral vessel wall. Recently, a new mutation in A beta, E22K, was identified in several Italian families that, like HCHWA-D, is associated with CAA and hemorrhagic stroke. These two similar disorders, stemming from amino acid substitutions at position 22 of A beta, implicate the importance of this site in the pathology of HCHWA. Previously we showed that HCHWA-D A beta(1-40) containing the E22Q substitution induces robust pathologic responses in cultured human cerebrovascular smooth muscle cells (HCSM cells), including highly elevated levels of cell-associated A beta precursor (A beta PP) and cell death. In the present study, a series of E22 mutant A beta(1-40) peptides were synthesized, and their pathogenic properties toward cultured HCSM cells were evaluated. Quantitative fluorescence analyses showed that mutant A beta(1-40) peptides either containing a loss of charge (E22Q and E22A) or a change of charge (E22K) bind to the surface of HCSM cells and form amyloid fibrils. Similarly, this same group of E22 mutant A beta(1-40) peptides caused enhanced pathologic responses in HCSM cells. In contrast, wild-type E22 or the charge-preserving E22D A beta(1-40) peptides were devoid of any of these pathogenic properties. These data suggest that a change or loss of charge at position 22 of A beta enhances the pathogenic effects of the peptide toward HCSM cells and may contribute to the pathogenesis of the phenotypically related HCHWA disorders.