Wang Z, Natté R, Berliner J A, van Duinen S G, Vinters H V
Department of Pathology and Laboratory Medicine, Neuropathology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1732, USA.
Stroke. 2000 Feb;31(2):534-8. doi: 10.1161/01.str.31.2.534.
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta protein (Abeta) in cortical and leptomeningeal vessels of patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type. Smooth muscle cells (SMC) from cerebral microvessels (MV) are of particular interest as a site of Abeta-related injury because CAA is much more pronounced in the tunica media of cortical arterioles than meningeal arteries. Patients carrying point mutations at residues 22 (E22Q) and 21 (A21G) of Abeta show severe CAA with various degrees of brain parenchymal Abeta deposition. The purpose of this study was to investigate the effects of 2 mutant E22Q- and A21G-Abeta peptides on MV and aortic SMC. MERHODS: SMC were isolated from human cerebral MV and aorta. Cell morphology, viability, and proliferation as parameters of Abeta toxicity were investigated after 3 days of peptide treatment by trypan blue exclusion and [(3)H]thymidine incorporation.
E22Q-Abeta induced significant decreased cellular proliferation and viability, as well as obvious degeneration of both MV and aortic SMC. A21G-Abeta and wild-type Abeta did not cause significant toxicity, as judged by cell morphology, viability, or cell proliferation, on either type of SMC.
E22Q-Abeta induced greater toxicity in all parameters than A21G-Abeta and wild-type Abeta with respect to both MV and aortic SMC. A21G-Abeta did not show a significant toxic effect on MV and aortic SMC. This differential effect may be linked to cell type-specific processing and metabolism of mutant forms of Abeta. Mutations in amyloid precursor protein may lead to CAA by different pathogenetic mechanisms or share an unknown property that distinguishes them from wild-type Abeta.
脑淀粉样血管病（CAA）的特征是淀粉样β蛋白（Aβ）沉积于阿尔茨海默病患者以及荷兰型遗传性淀粉样变性脑出血患者的皮质和软脑膜血管中。脑微血管（MV）的平滑肌细胞（SMC）作为Aβ相关损伤的一个部位特别受关注，因为CAA在皮质小动脉的中膜比脑膜动脉中更为明显。携带Aβ第22位残基（E22Q）和第21位残基（A21G）点突变的患者表现出严重的CAA，并伴有不同程度的脑实质Aβ沉积。本研究的目的是探讨两种突变型E22Q - 和A21G - Aβ肽对MV和主动脉SMC的影响。方法：从人脑MV和主动脉中分离出SMC。在肽处理3天后，通过台盼蓝排斥法和[³H]胸腺嘧啶核苷掺入法，研究细胞形态、活力和增殖作为Aβ毒性参数的情况。结果：E22Q - Aβ导致细胞增殖和活力显著降低，以及MV和主动脉SMC明显退变。根据细胞形态、活力或细胞增殖判断，A21G - Aβ和野生型Aβ对两种类型的SMC均未引起明显毒性。结论：就MV和主动脉SMC而言，E22Q - Aβ在所有参数上诱导的毒性均大于A21G - Aβ和野生型Aβ。A21G - Aβ对MV和主动脉SMC未显示出明显毒性作用。这种差异效应可能与Aβ突变形式的细胞类型特异性加工和代谢有关。淀粉样前体蛋白中的突变可能通过不同的致病机制导致CAA，或者具有将它们与野生型Aβ区分开来的未知特性。
