Abeta oligomers (ADDLs) in Alzheimer's Disease pathology

描述（由申请人提供）：本申请涉及阿尔茨海默病（AD）不同阶段个体大脑和脑脊液中β寡聚物（ADDLs）的病理积累。65岁以上的老年人中有10%患有这种疾病，给家庭带来痛苦的情感负担，每年给国家造成的损失超过1000亿美元。尽管阿尔茨海默病影响严重，但我们与之抗争的能力仍受到诊断不准确和治疗不充分的影响。目前的项目通过研究addl的临床特性来解决这些问题，我们确定addl是在AD脑和脑脊液中积累的亚稳态神经毒素。现在看来，adls可能在导致阿尔茨海默氏症逐渐灾难性痴呆的神经元功能障碍和损伤中发挥重要作用（卫生与人类服务2004-2005年阿尔茨海默病进展报告）。为了进一步加深我们对这种致病作用的理解，我们提出验证ADDLs对突触的攻击引发tau过度磷酸化、氧化损伤和突触退化的假设，从而为记忆衰竭和AD神经病理学的主要方面提供一个全面的机制。这一假设得到了细胞生物学和神经病理学研究结果的有力支持，将主要使用人类addl和中枢神经系统样本进行研究，以直接建立临床相关性。我们还建议研究为什么受ad影响的大脑无法清除addl，跟进新报道的神经病理学数据，表明神经胶质清除机制失败。基于最近的研究结果，我们的七个目标是：(i)验证脑脊液/血浆中的addl提供可靠的AD生物标志物；（ii）验证AD最早的临床前体征是单个神经元周围的ADDL积聚；（iii）验证被addl包围的神经元发生AD病理的预测；（iv）证实神经周围的ADDL沉积是由于ADDL附着在突触上；查明具有重要致病意义的寡聚物种类（假定为12聚物），并获得专门针对与疾病有关的寡聚物的新的单克隆抗体；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；（vii）确认在星形胶质细胞中发现的与ADDL相关的新病理，测试其与疾病发生和进展中ADDL清除机制失败的相关性。重要的技术创新包括基于超灵敏纳米技术的ADDL检测，溶液中针对ADDL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。研究结果有望为验证和优化adls作为阿尔茨海默病诊断和疾病改善治疗的主要靶点提供重要的进展。公共卫生相关性：该应用涉及β寡聚物（ADDLs）在阿尔茨海默病中的作用，重点关注人类样本，以建立直接的临床和病理相关性。从人类ADDL和组织中获得的结果将有助于回答ADDL参与发病机制的重要问题，并为未来的诊断和治疗证实ADDL的靶向性。

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.