Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.-猫眼课题宝

DOI：

10.1007/978-3-540-37652-1_29

发表时间：

1990-06

期刊：

Science

影响因子：

56.9

通讯作者：

中科院分区：

综合性期刊1区

文献类型：

作者：

E. Levy;M. Carman;I. Fernandez‐Madrid;M. Power;I. Lieberburg;S. V. van Duinen;G. Bots;W. Luyendijk;B. Frangione

1983年，从冰岛患者尸检时获得的脑血管中提取了第一个脑淀粉样蛋白分子，这些患者死于由于血管壁中半胱氨酸蛋白酶抑制剂C纤维沉积引起的大面积脑出血（Cohen et al. 1983），这是一种称为遗传性脑出血伴淀粉样变性（HCHWA）的疾病。这项研究的重要性超出了鉴定与脑淀粉样蛋白疾病相关的分子：它描述了一种从软脑膜血管中提取淀粉样蛋白的新颖而简单的方法，一年后G. Glenner等人从AD脑的软脑膜中分离出Aβ（Glenner和Wong 1984 a），最近为建立氨基酸取代与家族性脑淀粉样变性之间的关系提供了基础。对冰岛HCHWA病例中沉积的胱抑素C的完整氨基酸序列分析揭示了与脑淀粉样变性相关的第一个突变，即亮氨酸取代谷氨酰胺（Ghiso等，1986）由于密码子68处的单个A至T颠换，（Levy等，1989）。1985年，在最初的半胱氨酸蛋白酶抑制剂C和Aβ报告后不久，我们从荷兰的家族性病例中获得了三个大脑，其临床病理特征与冰岛病例非常相似，例如，脑淀粉样血管病（CAA）的反复发作，其特征提示HCHWA-荷兰型可命名为该病。值得注意的是，淀粉样蛋白沉积物不能被胱抑素C抗体识别，但能与Aβ抗体发生免疫反应（图1a）。提取的软脑膜材料的氨基酸序列分析证实了其Aβ特性（图1 e），免疫组织化学研究证实CAA与广泛的实质前淀粉样蛋白（非纤维状，刚果红阴性）沉积物共存，不存在神经炎斑块和神经纤维缠结。我们假设HCHWA-荷兰型是AD的血管变异型（货车Duinen et al. 1987）。进一步的研究发现APP基因密码子693处的点突变，即单核苷酸颠换（G为C），导致Aβ序列第22位的谷氨酸替换为谷氨酰胺（Kang等人，1987年; Levy等人，1990年; Prelli et al. 1990）和限制性片段长度多态性检测到的APP基因与疾病的紧密连锁（货车Broeckhoven et al. 1990）。Dutch突变的研究有助于确定血管沉积物中存在较短的Aβ种类（Prelli et al. 1988），以确定野生型和突变型APP可能具有不同的表型表现，并为发现未来的许多APP核苷酸取代铺平道路（在Goate章节中描述）。此外，本发明还提供了一种方法，

The first cerebral amyloid molecule identified was extracted in 1983 from cerebral blood vessels obtained at autopsy from Icelandic patients who died from massive brain hemorrhages due to the deposition of cystatin C fibrils in the vessel walls (Cohen et al. 1983), a condition referred to as hereditary cerebral hemorrhage with amyloidosis (HCHWA). The importance of this study extended beyond the identification of a molecule linked to a cerebral amyloid disease: it described a novel and simple method to extract amyloid from leptomeningeal vessels, a protocol that a year later was used by G. Glenner to isolate Aβ from leptomeninges obtained from AD brains (Glenner and Wong 1984a) and has lately provided the basis to establish the relationship between amino acid substitutions and familial cerebral amyloidosis. Complete amino acid sequence analysis of the deposited cystatin C in the Icelandic cases of HCHWA revealed the first mutation associated with cerebral amyloidosis, the replacement of leucine for glutamine (Ghiso et al. 1986) due to a single A to T transversion at codon 68 (Levy et al. 1989).In 1985, shortly after the initial cystatin C and Aβreports, we received three brains from familial cases in Holland exhibiting clinico-pathological features that closely resembled the Icelandic cases, eg, recurrent episodes of cerebral hemorrhages associated with overwhelming cerebral amyloid angiopathy (CAA), features that suggested the name HCHWA-Dutch type to designate the disease. Notably, amyloid deposits were not recognized by antibodies to cystatin C but were immunoreactive with antibodies to Aβ (Fig. 1a). Whereas amino acid sequence analysis of the extracted leptomeningeal material corroborated its Aβ identity (Fig. 1e), immunohistochemical studies verified the co-existence of CAA with widespread parenchymal pre-amyloid (non-fibrillar, Congo red negative) deposits in the absence of neuritic plaques and neurofibrillary tangles. We postulated that HCHWA-Dutch type is a vascular variant of AD (van Duinen et al. 1987). Further studies revealed a point mutation at codon 693 of the APP gene, a single nucleotide transversion (G for C) resulting in the replacement of glutamate for glutamine at position 22 of the Aβ sequence (Kang et al. 1987; Levy et al. 1990; Prelli et al. 1990) and a tight linkage of the APP gene with the disease detected by restriction fragment length polymorphism (Van Broeckhoven et al. 1990). The studies with the Dutch mutation helped to establish the existence of shorter Aβ species in vascular deposits (Prelli et al. 1988), to ascertain that wild-type and mutant APP can have different phenotypic presentation and to pave the way for the discovery of the many APP nucleotide substitutions to come (described in Goate’s Chapter). In addition,

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.

文献摘要

被引文献

相似文献