Complement and Inflammatory Factors in AD Pathogenesis

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的与认知功能进行性丧失相关的年龄相关的神经退行性疾病，目前仅在美国就有多达500万人受到影响。在AD脑中观察到的特征性神经病理学变化包括突触和神经元损失、神经元缠结（NFT）、由淀粉样蛋白（A）沉积物组成的细胞外老年斑和炎症事件的证据。这些病理标志物对AD中认知功能障碍的相对贡献仍然存在争议，但AD患者和AD转基因小鼠模型的研究结果表明，可能是多个重叠过程导致神经元变性和认知丧失。在人类研究中，临床上显著的认知能力下降发生在存在纤维状A？斑块和NFT的疾病阶段;然而，越来越明显的是，纤维状斑块的存在不足以用于AD的临床诊断，因此，该领域的大多数人现在承认，其他因素也是认知能力丧失的关键因素。我们最近的研究表明，PMX 205，一种小分子量的环状六肽C5 a受体（CD 88）拮抗剂，治疗显着减少神经病理学和改善表现在被动回避任务的背景记忆转基因小鼠模型的AD相对于未经处理的转基因动物。结果支持以下假设：抑制C5 a诱导的炎症减少淀粉样蛋白和缠结积累，减少突触丢失，并有助于预防或挽救海马依赖性记忆任务中的缺陷。当在这些模型中斑块通常积累的时间段内递送药物时发生这些作用的事实表明，抑制补体诱导的炎症可能会大大减缓AD中认知下降的“滚雪球”级联，即使在诊断出损伤的初始阶段之后。该治疗靶点与其他大量研究的AD治疗方法不同。到目前为止，PMX 205对CD 88/C5 aR具有特异性，这与可能影响可能具有有害的“脱靶”效应的靶标的其他提出的抑制剂（例如激酶抑制剂、半胱天冬酶抑制剂和较低特异性的免疫抑制剂）形成对比。该提案的具体目的是定义药物是否通过在外周或在脑本身内起作用而提供其有益作用，确定药物何时进入脑以及药物是否在延长的时间段内有效，评估药物是否可以在AD的动物模型中“逆转”认知丧失或仅仅停止/减缓疾病的进展，最后描述所涉及的细胞类型（神经元或神经胶质）并确定药物在减缓神经病理学进展中的分子作用机制。也就是说，该更新项目的中心目标是研究组分活化片段受体（CD 88）的拮抗剂作为治疗阿尔茨海默病（AD）的治疗靶点的潜力，并优化针对阻断由补体活化介导的促炎信号传导的治疗策略。 公共卫生相关性：仅在美国，估计就有500万人患有阿尔茨海默病，这是最常见的与年龄相关的痴呆症。在美国，阿尔茨海默病的成本估计为每年1480亿美元。先前研究期间的研究发现，补体系统激活片段的环状六肽拮抗剂在2种小鼠模型中减少病理学和避免认知丧失方面具有良好的效果。因此，目前的建议将集中在进一步的临床前评价这种特定的试剂，开发和评价新的化合物，靶向这种特定的受体，并验证的基本机制（S）的有益效果发生。

DESCRIPTION (provided by applicant): Alzheimer Disease (AD) is the most common age-related neurodegenerative disorder associated with progressive loss of cognitive function, which currently afflicts up to 5 million people in the US alone. Characteristic neuropathological changes seen in AD brain include synaptic and neuronal loss, neurofibrillary tangles (NFTs), extracellular senile plaques composed of amyloid (A¿) protein deposits and evidence of inflammatory events. The relative contributions of these pathological markers to the cognitive dysfunction in AD remains controversial, but results from studies in both AD patients and transgenic mouse models of AD, make it likely that multiple, overlapping processes contribute to neuronal degeneration and cognitive loss. In human studies, clinically significant cognitive decline occurs at the stage of the disease in which fibrillar A¿ plaques and NFT are present; however, it is becoming increasingly evident that the presence of fibrillar plaques is not sufficient for clinical diagnosis of AD, and, thus it is now acknowledged by most in the field that other factors are also critical in loss of cognition. Our recent studies demonstrated that treatment with PMX205, a small molecular weight cyclic hexapeptide C5a receptor (CD88) antagonist, significantly reduced neuropathology and improved performance in a passive avoidance task for contextual memory in transgenic mouse models of AD relative to untreated transgenic animals. The results support the hypothesis that the inhibition of C5a-induced inflammation reduces amyloid and tangle accumulation, reduces synapse loss, and contributes to the prevention or rescue of a deficit in a hippocampal dependent memory task. The fact that these effects occur when the drug was delivered during the period of time that plaques are normally accumulating in these models, suggests that inhibition of complement-induced inflammation might substantially slow the "snowballing" cascade of cognitive decline in AD, even after the initial stages of impairment are diagnosed. This therapeutic target is distinct from other heavily investigated approaches for AD therapies. Thus far, PMX205 is specific for CD88/C5aR in contrast to other proposed inhibitors that may affect a target (s) that can have detrimental "off target" effects such as kinase inhibitors, caspase inhibitors, and less specific immune suppressors. The specific aims of this proposal are to define whether the drug provides its beneficial action by acting in the periphery or within the brain itself, determine at what time the drug gains access to the brain and whether the drug is effective for extended periods of time, assess whether the drug can "reverse" cognitive loss in an animal model of AD or merely stop/slow progression of the disease, and finally to delineate the cell types (neurons or glia) involved and define the molecular mechanism of action of the drug in slowing the progression of neuropathology. That is, the central goal of this renewal project is to investigate the potential of an antagonist to a component activation fragment receptor (CD88) as a therapeutic target for treatment of Alzheimer Disease (AD) and to optimize a therapeutic strategy directed at blocking the proinflammatory signaling mediated by complement activation. PUBLIC HEALTH RELEVANCE: In the U.S. alone, it is estimated that 5 million people are afflicted with Alzheimer's Disease, the most common form of age-related dementia. The cost of Alzheimer's Disease is estimated 148 billion dollars annually in the US. Studies in the previous research period discovered promising effects of a cyclic hexapeptide antagonist of a complement system activation fragment in reducing pathology and avoiding cognitive loss in 2 mouse models. Thus, the current proposal will focus on further preclinical evaluation of this specific reagent, development and evaluation of new compounds that target this specific receptor, and validation of the fundamental mechanism(s) by which the beneficial effect occurs.