ROLE OF PRE FIBRILLAR AMYLOID IN ALZHEIMER'S DISEASE

前纤维状淀粉样蛋白在阿尔茨海默病中的作用

• 批准号: 6229503
• 负责人: DEAN M HARTLEY
• 金额: $ 8.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-12 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6229503
• 关键词: Alzheimer's disease; amyloid proteins; calcium flux; cerebrospinal fluid; disease /disorder etiology; embryo /fetus tissue /cell culture; genetically modified animals; human fetus tissue; laboratory mouse; membrane channels; neuritic plaques; neurofibrillary tangles; neuropathology

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.

描述：(逐字摘自申请者摘要)阿尔茨海默病(AD) 是一种缓慢进展的疾病，无论是在组织病理学上还是临床上。早些时候 症状包括轻度记忆丧失和认知障碍，进展很快 潜伏到严重的痴呆症。生化和结构研究表明 临床症状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，可能包括神经元性营养不良，突触 丢失和/或坦率的细胞死亡(Anderton等人，1998年；Morris et.艾尔1996年)。这个 这种进行性病理生理学的基本机制被认为是 是一种与年龄相关的淀粉样β蛋白(Abeta)纤维堆积， 最终在尸检中观察到成熟的淀粉样斑块。然而，关注的焦点是 终末期组织导致了这样的假设，即纤维本身是 AD的进展。我们的工作假设是低分子质量的Abeta (单体/二聚体)转变为前纤维状、低聚形式的Abeta，可以 引发神经元功能障碍，并可直接和/或通过进一步转变为 相对分子质量较高的聚合物(纤维)会引发神经元丢失。在支持中 其中，已在AD患者的脑脊液中发现了Abeta寡聚体 患者，前纤维形式的Abeta导致突触功能障碍和神经元 死亡和大脑中的可溶性Abeta水平与 认知障碍。此外，我们最近发表了一种亚稳态 低聚形式的Abeta，原纤维蛋白(PF)，可以显著增加 大脑皮层神经元的电活动并可重复地引起神经毒性。 在这份提案中，我们将通过关注以下方面来扩展我们的初步数据：1) 神经细胞功能障碍和损伤的早期标志物鉴定 Abeta的前纤维形式，2)受体拮抗这种损伤 拮抗剂和3)自然产生的稳定性的生物学特性 培养物中的Aβ寡聚体。我们的模型和数据表明，早产儿和 阿尔茨海默病的临床进展部分是由早期的时间变化驱动的 发生在Abeta物种中，而不仅仅是坦率的Abeta原纤维形成。破译 而阻断PF的生物活性是一种应该有所帮助的新方法 在阐明早期Abeta中间体在AD和设计中的作用 合理的治疗策略，以减缓或阻止AD的进展。