Complement and Inflammatory Factors in AD Pathogenesis

描述(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有关的与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。AD脑内典型的神经病理改变包括突触和神经元的丢失、神经原纤维缠结(NFT)、由淀粉样蛋白(A)沉积组成的细胞外老年斑和炎症事件的证据。这些病理标记物在AD认知功能障碍中的相对作用仍存在争议，但在AD患者和AD转基因小鼠模型上的研究结果表明，多个重叠的过程可能导致神经元退化和认知丧失。在人类研究中，临床上显著的认知功能下降发生在疾病的阶段，其中存在纤维斑块和NFT；然而，越来越明显的是，纤维斑块的存在不足以作为AD的临床诊断，因此，现在该领域的大多数人承认，其他因素也是导致认知丧失的关键因素。我们最近的研究表明，与未治疗的转基因动物相比，小分子量环六肽C5a受体(CD88)拮抗剂PMX205显著降低了转基因AD小鼠模型的神经病理改变，并改善了对上下文记忆的被动回避任务。这些结果支持这样一种假设，即抑制C5a诱导的炎症可以减少淀粉样蛋白和缠结的积累，减少突触丢失，并有助于预防或挽救海马依赖记忆任务中的缺陷。当药物在这些模型中正常积累斑块的时间段内给药时，这些效应就会发生，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功能下降的“滚雪球”级联反应，即使在最初的损害被诊断出来之后。这一治疗靶点有别于其他经过大量研究的AD治疗方法。到目前为止，PMX205是针对CD88/C5aR的，而其他建议的抑制剂可能会影响靶点(S)，这些靶点可能具有有害的“脱靶”效应，如激酶抑制剂、半胱氨酸天冬氨酸氨基转移酶抑制剂和特异性较低的免疫抑制物。这项建议的具体目的是确定药物是通过在外周还是在大脑内发挥作用来提供有益的作用，确定药物何时进入大脑以及药物是否在较长时间内有效，评估药物是否可以在AD动物模型中“逆转”认知损失，或者仅仅是阻止/减缓疾病的进展，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方面的分子作用机制。也就是说，这个更新项目的中心目标是研究成分激活片段受体(CD88)的拮抗剂作为阿尔茨海默病(AD)治疗靶点的潜力，并优化旨在阻断补体激活介导的促炎信号的治疗策略。 与公共健康相关：据估计，仅在美国就有500万人患有阿尔茨海默病，这是最常见的老年痴呆症。在美国，阿尔茨海默氏症每年造成的损失估计为1480亿美元。前一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只小鼠模型中具有减少病理和避免认知丧失的良好效果。因此，目前的建议将集中在对这种特定试剂的进一步临床前评估，针对这种特定受体的新化合物的开发和评估，以及对产生有益效果的基本机制的验证(S)。

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.