Abeta oligomers (ADDLs) in Alzheimer's Disease pathology

描述（由申请人提供）：本申请涉及在阿尔茨海默病（AD）的不同阶段的个体的脑和CSF中Abeta寡聚体（ADDL）的病理学积累。这种疾病袭击了10%的65岁以上的人，给家庭带来痛苦的情感负担，每年给国家造成超过1000亿美元的损失。尽管其严重的影响，我们的能力，以应付AD遭受不精确的诊断和治疗不足。目前的项目通过研究ADDL的临床特性来解决这些问题，我们将其鉴定为在AD脑和CSF中积累的亚稳态神经毒素。现在看来，ADDL可能在导致AD的渐进性灾难性痴呆的神经元功能障碍和损伤中起重要作用（Health & Human Services 2004-2005 Progress Report on Alzheimer's Disease）。为了推进我们对这种致病作用的理解，我们建议测试ADDLs对突触的攻击引发tau蛋白过度磷酸化、氧化损伤和突触退化的假设，从而为记忆障碍和AD神经病理学的主要方面提供全面的机制。这一假说得到了细胞生物学和神经病理学研究结果的有力支持，将主要使用人ADDL和CNS样本进行研究，以直接确定临床相关性。我们还建议调查为什么AD影响的大脑是无法删除ADDLs，跟进新报道的神经病理学数据表明胶质清除机制失败。基于最近的结果，我们的七个目标是：（i）证实CSF/血浆中的ADDL提供可靠的AD生物标志物;（ii）验证AD的最早临床前体征是单个神经元周围的ADDL积累;（iii）测试被ADDL包围的神经元发展AD病理的预测;（iv）验证ADDL的神经元周沉积是由于ADDL附着于突触;（v）确定致病性显著的寡聚物种类（vi）测试突触膜蛋白在ADDLS仅攻击特定神经元的机制中的预测作用;和（vii）确认在星形胶质细胞中发现的新的ADDL相关病理学，测试其与疾病发作和进展中失败的ADDL清除机制的相关性。重要的技术创新包括超灵敏的基于纳米技术的ADDL测定，对溶液中ADDL具有特异性的单克隆抗体，以及一系列能够在不使用SDS或其他刺激性化学品的情况下表征稀水溶液中低聚物大小的物理化学方法。预计结果将提供验证和优化ADDL作为阿尔茨海默病诊断和疾病修饰疗法的主要靶点所需的重要进展。公共卫生相关性：本申请涉及Abeta寡聚体（ADDL）在阿尔茨海默氏病中的作用，重点是人类样品以建立直接的临床和病理相关性。用人类ADDL和组织获得的结果将有助于回答ADDL参与发病机制的重要问题，并证实ADDL的靶向用于未来的诊断和治疗。

DESCRIPTION (provided by applicant): This application concerns the pathological accumulation of Abeta oligomers (ADDLs) in brains and CSF of individuals at various stages of Alzheimer's disease (AD). This disease strikes 10 percent of individuals over 65, inflicting painful emotional burden to families and a cost to the country of more than $100 billion annually. Despite its serious impact, our ability to contend with AD suffers from imprecise diagnostics and inadequate therapeutics. The current project addresses these problems by investigating the clinical properties of ADDLs, which we identified as metastable neurotoxins that accumulate in AD brain and CSF. It now appears likely that ADDLs play a significant role in the neuronal dysfunction and damage responsible for AD's progressively catastrophic dementia (Health & Human Services 2004-2005 Progress Report on Alzheimer's Disease). To advance our understating of this pathogenic role, we propose to test the hypothesis that an attack on synapses by ADDLs initiates tau hyperphosphorylation, oxidative damage and synapse deterioration, thus providing a comprehensive mechanism for memory failure and the major facets of AD neuropathology. This hypothesis, which is strongly supported by findings from cell biology and neuropathology, will be investigated primarily using human ADDLs and CNS samples in order to directly establish clinical relevance. We also propose to investigate why AD-affected brain is unable to remove ADDLs, following up on newly reported neuropathological data suggesting a failure of glial clearance mechanisms. Building on recent results, our seven aims are to: (i) Validate that ADDLs in CSF/plasma provide a reliable AD biomarker; (ii) Verify that the earliest preclinical sign of AD is ADDL accumulation around individual neurons; (iii) Test the prediction that neurons surrounded by ADDLs develop AD pathology; (iv) Verify that perineuronal deposits of ADDLs are due to ADDL attachment to synapses; (v) Identify the pathogenically significant oligomeric species (putatively 12mers) and obtain new monoclonal antibodies that specifically target disease-relevant oligomers; (vi) Test the predicted role of synaptic membrane proteins in the mechanism by which ADDLS attack only particular neurons; and, (vii) Confirm the novel ADDL-related pathology discovered in astrocytes, testing its relevance to failed ADDL clearance mechanisms in disease onset and progression. Important technical innovations include ultrasensitive nanotechnology-based ADDL assays, monoclonal antibodies specific for ADDLs in solution, and a series of physicochemical methods capable of characterizing oligomer size in dilute aqueous solutions without the use of SDS or other harsh chemicals. Results are expected to provide important advances needed to validate and optimize ADDLs as major targets for Alzheimer's diagnostics and disease-modifying therapeutics. PUBLIC HEALTH RELEVANCE: This application concerns the role of Abeta oligomers (ADDLs) in Alzheimer's disease, focusing on human samples to establish direct clinical and pathological relevance. Results obtained with human ADDLs and tissue will help answer important questions central to ADDL involvement in pathogenesis and substantiate the targeting of ADDLs for future diagnostics and therapeutics.