Complement and Inflammatory Factors in AD Pathogenesis

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病，与认知功能的进行性丧失有关，目前仅在美国就有多达500万人患有此病。AD脑的特征性神经病理改变包括突触和神经元丢失、神经原纤维缠结（nft）、由淀粉样蛋白沉积组成的细胞外老年斑和炎症事件的证据。这些病理标记物对阿尔茨海默病患者认知功能障碍的相对作用仍存在争议，但对阿尔茨海默病患者和阿尔茨海默病转基因小鼠模型的研究结果表明，多个重叠的过程可能导致神经元变性和认知丧失。在人体研究中，临床上显著的认知能力下降发生在纤维A¿斑块和NFT存在的疾病阶段；然而，越来越明显的是，纤维斑块的存在不足以作为阿尔茨海默病的临床诊断，因此，现在该领域的大多数人都承认，其他因素在认知丧失中也很重要。我们最近的研究表明，相对于未治疗的转基因动物，PMX205（一种小分子量环六肽C5a受体（CD88）拮抗剂）治疗可显著降低AD转基因小鼠模型的神经病理学，并提高其在被动回避任务中上下文记忆的表现。该结果支持了c5a诱导的炎症抑制减少淀粉样蛋白和缠结积累，减少突触损失，并有助于预防或挽救海马依赖性记忆任务中的缺陷的假设。事实上，当药物在这些模型中斑块通常积聚的时间段内传递时，这些效果就会发生，这表明，抑制补体诱导的炎症可能会大大减缓阿尔茨海默病认知能力下降的“滚雪球”级联，即使在诊断出损害的初始阶段之后。这种治疗靶点不同于其他经过大量研究的阿尔茨海默病治疗方法。到目前为止，PMX205对CD88/C5aR具有特异性，而其他可能影响靶标的抑制剂（如激酶抑制剂、caspase抑制剂和特异性较低的免疫抑制剂）可能具有有害的“脱靶”效应。该提案的具体目的是确定药物是通过作用于外周还是在大脑内部提供有益作用，确定药物何时进入大脑以及药物是否在较长时间内有效，评估药物是否可以“逆转”AD动物模型中的认知丧失或仅仅阻止/减缓疾病进展。最后描述所涉及的细胞类型（神经元或胶质细胞），并确定药物在减缓神经病理进展中的分子作用机制。也就是说，本更新项目的中心目标是研究成分激活片段受体（CD88）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激活介导的促炎信号传导的治疗策略。

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.