ROLE OF PRE FIBRILLAR AMYLOID IN ALZHEIMER'S DISEASE

描述：（申请人摘要中的逐字记录）阿尔茨海默病（AD） 在组织病理学和临床上都是一种缓慢进展的疾病。早期 症状包括轻微的记忆丧失和认知障碍， 严重的痴呆症。生化和结构研究表明 临床病理学最初可能是由于突触功能障碍，其次是 更深刻的神经元变化，可能包括神经炎性营养不良，突触 损失和/或明显的细胞死亡（安德顿等人，1998; Morris et. 1996）。的 这种进行性病理生理学的基本机制被认为 是淀粉样β蛋白（Abeta）纤维的年龄相关性积累， 最终在尸检中观察到成熟的淀粉样斑块。然而，重点是 终末期组织导致了这样的假设，即原纤维本身是 AD的进展。我们的假设是低分子量的Abeta （单体/二聚体）转变为Abeta的前纤维状低聚物形式， 引发神经元功能障碍，并可直接和/或通过进一步转变为 更高分子量的聚合物（原纤维）触发神经元损失。支持 其中，已在AD的脑脊液中鉴定出Abeta寡聚体 在患者中，Abeta的前纤维形式引起突触功能障碍和神经元功能障碍。 死亡和脑中可溶性Abeta水平与 认知障碍此外，我们最近发表了一个亚稳态， Abeta的寡聚体形式，即原纤维（PF），可以急剧增加 皮质神经元的电活动，并可重复地诱导神经毒性。 在本提案中，我们将通过关注以下方面来扩展我们的初步数据：1） 诱导的神经元功能障碍和损伤的早期标志物的鉴定 A β的前纤维形式，2）受体对这种损伤的拮抗作用 拮抗剂和3）天然产生的稳定的生物学表征 培养物中的Abeta寡聚体。我们的模型和数据表明， AD的临床进展部分由早期时间变化驱动 发生在Abeta物种中，而不仅仅是坦率的Abeta原纤维形成。解密 阻断PF的生物活性是一种新的方法， 在阐明早期Abeta中间体在AD中的作用和设计 合理的治疗策略来减缓或阻断AD的进展。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Alzheimer's disease (AD) is a slowly progressive disease, both histopathologically and clinically. Early symptoms include mild memory loss and cognitive impairment that progress very insidiously to severe dementia. Biochemical and structural studies suggest clinical symptomology may initially be due to synaptic dysfunction, followed by more profound neuronal changes, that may include neuritic dystrophy, synaptic loss, and/or frank cell death (Anderton et al.,1 998; Morris et. al. 1996). The fundamental mechanism underlying this progressive pathophysiology is thought to be an age-related accumulation of amyloid beta-protein (Abeta) fibrils, ultimately observed as mature amyloid plaques at autopsy. However, the focus on end-stage tissue has led to the assumption that fibrils per se underlie the progression of AD. Our working hypothesis is that low molecular weight Abeta (monomer/dimer) transitions to prefibrillar, oligomeric forms of Abeta that can initiate neuronal dysfunction and can directly and/or via further transition to higher molecular weight polymers (fibrils), trigger neuronal loss. In support of this, Abeta oligomers have been identified in the cerebrospinal fluid of AD patients, prefibrillar forms of Abeta cause synaptic dysfunction and neuronal death, and soluble Abeta levels in brain correlate relatively well with cognitive impairment. Furthermore, we recently published that a metastable oligomeric form of Abeta, protofibrils (PF), can acutely increase the electrical activity of cortical neurons and reproducibly induce neurotoxicity. In this proposal, we will extend our preliminary data by focusing on: 1) identification of early markers of neuronal dysfunction and injury induced by prefibrillar forms of Abeta, 2) antagonism of this injury byreceptor antagonists and 3) biological characterization of naturally generated stable Abeta oligomers in culture. Our model and data suggest that the preelinical and clinical progression of AD is driven, in part by early temporal changes occurring in Abeta species, not just frank Abeta fibril formation. Deciphering and blocking the biological activity of PF is anovel approach that should help in elucidating the role of early Abeta intermediates in AD and in designing rational therapeutic strategies to slow or block the progression of AD.