AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING

描述（研究者摘要）：最常见的淀粉样变性是 阿尔茨海默病（AD），其中A β是阿尔茨海默病的主要成分。 淀粉样蛋白 自1985年以来，我们的工作假设是， AD的发病机制是A β的固有纤维形成， 影响纤维形成的因素。 我们提出， AD和唐氏综合征（Down's syndrome，DS）是指神经病理学的进展， 病变首先经历类扁桃体阶段，在非 纤维状的 这些病变经历逐渐压实， 纤维化，产生老年斑， 神经元功能障碍和死亡。 神经纤维缠结（NFT）形成 这似乎是后来的变化。 我们在系统化方面的丰富经验 淀粉样变性和对家族性AD荷兰变体的研究使我们 结论是血管来源的A β有助于 对嗜酸性血管病和老年斑都有显著影响。 正如我们 预测，最近发现具有相同氨基酸的肽 作为A β的酸性序列作为正常可溶性蛋白（sA β）存在于 生物液体 这将AD与一些系统性的 淀粉样变性，其中淀粉样前体在循环中被发现 正常情况下 因此，目前AD研究的一个关键问题是什么因素 在疾病状态下改变s A β，促进聚集，淀粉样蛋白 形成和脑毒性。 已经发现了许多突变， A β前体（β PP）基因，与早发性 家族AD 然而，A β沉积通常发生在缺乏 β PP基因突变 因此，其他因素更重要， 大多数AD患者。 因此，我们打算通过生物化学， 免疫组织化学和超微结构方法， sA β沉积和与之相关的事件 类胶质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（apo） 1991年，我们提出apoE是A β分子伴侣 用于促进和/或稳定β-折叠片层的蛋白质 结构 这一假设得到了以下发现的支持： apoE的同种型E4与晚发型家族性和 零星AD。 另一方面，我们已经确定了一个主要的 sA β携带者另外，我们对A β的体外研究 肽已经鉴定出正常组织中的聚集抑制剂或“去聚集蛋白”， 生物液体我们假设在各种因素之间存在一种平衡 其促进纤维形成，例如ApoE和去聚集蛋白。 这些 相互作用可能是决定为什么sA β最初 沉积为类神经胶质以及为什么类神经胶质进展为神经炎 斑块形成 我们建议研究以下内容：I）生物化学和 无症状性甲状腺肿中类淀粉样蛋白和淀粉样蛋白免疫组化研究 老年人，唐氏综合征，AD患者和AD的老年狗模型。（二） 构象改变和/或翻译后改变的鉴定 正常老年人和个体中sA β的修饰，包括 sA β水平及其伴侣蛋白鉴定的研究 在正常和疾病状态下。3)A β和 病理性伴侣，特别是载脂蛋白E， 对淀粉样蛋白形成和纤维形成至关重要。 研究者将提供与以下疾病相关的发病机制： AD脑淀粉样沉积、淀粉样血管病和正常衰老。的 这项研究还可能提供一种诊断测试和新的 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.