AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING

描述(研究人员摘要)：最常见的淀粉样变性是 阿尔茨海默病(AD)，其中Aβ是 淀粉样蛋白。自1985年以来，我们的工作假说一直是 阿尔茨海默病的发病机制是Aβ和Aβ的固有纤维形成 影响原丝形成的因素。我们在 AD和唐氏综合征(DS)的神经病理进展 皮损首先经历前叶样体阶段，在非 纤维状的。这些损伤经历了逐渐的压缩和 纤维化，产生与之相关的衰老斑块 神经元功能障碍和死亡。神经原纤维缠结(NFT)形成 似乎是后来的变化。我们在系统管理方面的丰富经验 淀粉样变性和对家族性AD的荷兰变体的研究使我们 结论是Aβ的血管来源有助于 对亲合性血管病和老年性斑块均有显著影响。因为我们 预测，最近发现具有相同氨基的多肽 酸序列以Aβ形式以正常的可溶性蛋白(Saβ)形式存在于 生物体液。这将AD与一些系统性的 淀粉样变性，在循环中发现淀粉样前体 通常是这样的。因此，目前AD研究中的一个关键问题是什么因素 改变S Aβ中的疾病状态，促进聚集，淀粉样蛋白 形成和脑毒性。在中国发现了许多突变 与早发相关的Aβ前体(βPP)基因 家族性AD。然而，Aβ沉积通常在不存在的情况下发生 贝塔PP基因突变。因此，其他因素在这些因素中更为重要 大多数AD患者。因此，我们打算通过生化手段来鉴定， 免疫组织化学和超微结构法检测致病因素 与Sa Beta沉积和与 前叶样病变进展为神经炎斑块。 最近我们的生化和免疫组织化学研究表明 两种载脂蛋白在淀粉样变性中的重要性：载脂蛋白 E和J.我们在1991年提出，载脂蛋白E是Aβ伴侣 蛋白质，起促进和/或稳定β-折叠薄片的作用 结构。这一假说得到了以下发现的支持：一个特定的 载脂蛋白E等位基因E4与晚发性家族性和 零星的AD。另一方面，ApoJ，我们已经确定为主要的 沙门氏菌携带者。此外，我们还进行了Aβ的体外研究 在正常情况下，多肽已识别出聚集抑制物或“去聚集素” 生物体液。我们假设各因素之间存在平衡。 促进纤维形成的物质，如ApoE和Desaggrins。这些 交互作用可能是确定为什么sa beta最初是 前叶样沉积及前叶样变为神经炎的原因 斑块形成。 我们建议研究以下几个方面：i)生化和 无症状患者前叶样蛋白和淀粉样蛋白的免疫组织化学研究 老年人、唐氏综合症、AD患者和老年犬AD模型。2) 识别构象变化和/或翻译后 正常老年人和个体的Saβ的修改，包括 Saβ水平及其伴侣蛋白鉴定的研究 在正常和疾病状态下。3)Aβ和Aβ之间的相互作用 病理性伴侣，特别是载脂蛋白E，它们是 对淀粉样蛋白形成和纤维形成至关重要。 调查人员将提供与以下相关的致病机制 阿尔茨海默病脑部淀粉样蛋白沉积，淀粉样血管病和正常衰老。这个 研究还可能提供诊断测试和新的 治疗方法。

DESCRIPTION (Investigator's Abstract): The most common amyloidosis is Alzheimer's disease (AD), where A beta is the major component of the amyloid. It has been our working hypothesis since 1985 that central to the pathogenesis of AD are the inherent fibrillogenesis of A beta and the factors which influence fibril formation. We put forward that in AD and Down's syndrome (DS) the progression of the neuropathological lesions goes first through the stage of preamyloid, which in non- fibrillar. These lesions undergo a gradual compaction and fibrillization, producing senile plaques that are associated with neuronal dysfunction and death. Neurofibrillary tangle (NFT) formation appears to be a later change. Our extensive experience with the systemic amyloidoses and work on the Dutch variant of familial AD has led us to the conclusion that a vascular source of A beta contributes significantly to both congophilic angiopathy and senile plaques. As we predicted, it has been recently found that peptides with the same amino acid sequence as A beta exist as a normal soluble protein (sA beta) in biological fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation normally. Hence a key question in AD research currently is what factors alter s A beta in the disease state, promoting aggregation, amyloid formation and cerebral toxicity. Numerous mutation have been found in the A beta precursor (beta PP) gene, associated with early onset familial AD. However, A beta deposition typically occurs in the absence of beta PP mutations. Therefore other factors are more important in the majority of AD patients. Thus, we intend to identify by biochemical, immunohistochemical and ultrastructural methods the factors which lead to sA beta deposition and the events which are associated with the progression of preamyloid lesions into neuritic plaques. Recently our biochemical and immunohistochemical studies have shown the importance of two apolipoproteins in amyloidosis: apolipoproteins (apo) E and J. We have proposed, in 1991, that apoE is an A beta chaperone protein, acting to promote and/or stabilize a beta-pleated sheet structure. This hypothesis is supported by the finding that a specific isotype of apoE, E4, is associated with late onset familial and sporadic AD. ApoJ, on the other hand, we have identified as a major carrier of sA beta. ln addition our in vitro studies with A beta peptides have identified aggregation inhibitors or "desaggins" in normal biological fluids. We hypothesize that a balance exists between factors which promote fibril formation, such as ApoE and desaggrins. These interactions may be critical to determining why sA beta is initially deposited as preamyloid and why preamyloid progresses on to neuritic plaque formation. We proposed to study the following: I) Biochemical and immunohistochemical studies of preamyloid and amyloid in asymptomatic elders, Down's syndrome, AD patients and in an aged dog model of AD. 2) Identification of the conformational alterations and/or posttranslational modifications of sA beta in normal elderly and individuals, including studies on sA beta levels and identification of its chaperone proteins in the normal and disease state. 3) The interactions between A beta and pathological chaperrones, in particular apolipoprotein E, which are critical to amyloid formation and fibrillogenesis. The investigators will provide etiopathogenic mechanisms associated with amyloid deposition the AD brain, amyloid angiopathy and normal aging. The study may also provide the possibility of a diagnostic test and new therapeutic approaches.