Statin modulation of immunotherapy for Alzheimer disease

描述(由申请人提供)： 阿尔茨海默病免疫治疗的他汀类药物调节摘要/摘要阿尔茨海默病(AD)是老年人最常见的痴呆性疾病，成为退伍军人的主要健康和/或保健问题。它的病理特征是大脑中存在细胞外老年斑，主要由40-42个氨基酸长度的淀粉样β蛋白(A(1-40，42)肽)组成。旨在清除A(斑块)或中和A的前体、可溶性或低聚形式的A(在斑块形成之前)的策略一直是阿尔茨海默病患者密集研究的重点。另一种不同的抗AD策略，接种A(肽)，也可以减少A(在AD转基因小鼠中的沉积，并改善认知。关于A(免疫治疗)作用的两个主要假说是通过Fc受体促进小胶质细胞吞噬作用和通过抗A(抗体外周血沉)增加脑/血浓度梯度促进A(从脑中清除)。这种疗法的临床试验因部分病例的脑部炎症而暂停。尽管有这种副作用，但这项试验的第一批报告表明，在减缓产生抗脑A抗体的患者的痴呆进展速度方面取得了一些成功(。我们的长期目标是验证这样一种假设，即联合抗A(疫苗接种)和洛伐他汀(抗CD40治疗)作为共同使用的AD免疫治疗策略将是互惠的，不仅可以消除疫苗可能导致的炎症，而且还可以改善AD模型小鼠的记忆障碍。洛伐他汀通过增加大脑中的抗炎细胞因子，以及通过减缓小胶质细胞成熟为促炎抗原呈递表型，预计可以消除抗A免疫疗法的潜在不良影响。此外，洛伐他汀介导的CD40信号干扰应通过极化处于吞噬状态的激活的小胶质细胞来增强A(抗体)的清除特性。这些作用将在体外和体内进行三个特定目标的测试，旨在充分表征洛伐他汀对CD40连接后小胶质细胞吞噬和抗原提呈表型的调节作用，包括细胞表面、细胞因子和小胶质细胞吞噬或抗原提呈状态特有的信号标记。此外，在存在和不存在洛伐他汀的情况下，将测量原代小胶质细胞对免疫球蛋白调理A的摄取。此外，我们将研究洛伐他汀治疗Tg2576小鼠后AD样病理的假定减少。最后，当洛伐他汀与A(疫苗)联合使用时，预计将出现相加或协同的治疗效果，这将通过比较A(疫苗接种和PBS免疫)Tg2576小鼠来检验，Tg2576小鼠接受洛伐他汀治疗或对照，并在几个年龄段处死。 公共卫生相关性： 项目简介阿尔茨海默病(AD)是一种慢性进行性痴呆，与记忆和行为障碍有关。目前约占所有痴呆症的70%，发病通常发生在中老年。在60岁以后，这种频率每五年增加一倍，从60岁个人约1%的患病率增加到85岁或以上人群约40%。因此，对于退伍军人和所有活过60岁的人来说，这种疾病都是一个明显的医疗问题。此外，随着人口老龄化的增长，阿尔茨海默病将成为一个更严重的社会经济问题。事实上，预计在21世纪中叶，随着中东的各种冲突，阿尔茨海默病的患病率将大幅上升。据预测，到那时，美国的AD患者数量将上升到1320万，这还不包括部署的美军监督人员。在退伍军人管理局医疗费用方面，据估计，仅与AD有关的直接和间接费用总额，以每个患者为基础，在整个病程中约为91,000美元。阿尔茨海默病的主要脑部异常被认为是大脑中主要由淀粉样β(A)多肽组成的细胞外老年斑的存在。针对这些斑块从大脑中清除的策略可能会帮助患有AD的患者。在老鼠模型中，我们有两种这样的策略。一种是接种A(肽)疫苗。我们发现，这减少了AD小鼠模型中的衰老斑块，同时改善了它们的记忆。第二种策略是使用一种常见的降胆固醇药物，即洛伐他汀。这也具有与接种疫苗类似的效果。然而，当大脑恢复时，这两种策略都是不够的，也看不到恢复正常行为的迹象。此外，由于严重的副作用，疫苗接种的临床试验被暂停，我们可能会通过添加洛伐他汀来克服这些副作用。因此，我们的长期目标是验证这样的假设，即联合接种疫苗和洛伐他汀治疗将在AD模型小鼠中作为联合应用的AD治疗将是互惠的。洛伐他汀被预测通过增加大脑中的抗炎化学物质来消除接种A(A)疫苗的潜在不良影响，并且应该比单独接种疫苗更进一步地减少记忆问题。这将通过比较几组小鼠的行为和脑健康来进行测试，这些组包括：A组(单独接种)和那些洛伐他汀加A组(接种。

DESCRIPTION (provided by applicant): Statin modulation of immunotherapy for Alzheimer disease Summary/Abstract Alzheimer's disease (AD) is the most common dementing illness in the elderly and becoming major veteran's health and/or healthcare issues. It is pathologically characterized by the presence of extracellular senile plaques in the brain primarily composed of 40-42 amino acid length amyloid beta (A(1-40, 42) peptides. Strategies targeting the clearance of A( plaques or neutralization of the precursor soluble or oligomeric forms of A( which precede plaque formation have been the focus of intense research for patients suffering from AD. A different anti-AD strategy, vaccination with the A( peptide, also reduces A( deposition in AD transgenic mice and improves cognition. Two major hypotheses regarding the actions of A( immunotherapy are the facilitation of microglial phagocytosis via Fc receptors and promotion of A( removal from the brain by increasing the brain/blood concentration gradient via anti-A( antibody peripheral sink. Clinical trials of this therapy were halted because of brain inflammation in subset of cases. In spite of this side-effect, the first reports form this trial suggested some success in slowing the rate of dementia progression in patients generating antibodies against brain A(. Our long-term objective is to test the hypothesis that combined anti-A( therapy (vaccination) and lovastaitn (anti-CD40 therapy) will be mutually beneficial as a co-administrated AD immunotherapy strategy in not only abrogating inflammation that may result from vaccination, but also in improving memory deficits in AD model mice. Lovastatin is predicted to abrogate the potential adverse effects of the anti-A( immunotherapy by increasing anti-inflammatory cytokines in the brain, as well as by slowing the maturation of the microglia into the pro-inflammatory antigen presenting phenotype. In addition, lovastatin-mediated disruption of CD40 signaling should enhance the A( clearing properties of A( antibodies by polarizing activated microglia in a phagocytic state. These actions will be tested in vitro and in vivo in three specific aims designed to fully characterize lovastatin modulation of microglial phagocytic and antigen presenting phenotypes following CD40 ligation in terms of cell surface, cytokine, and signaling markers specific to phagocytic or antigen presenting states of microglia. Further the uptake of IgG-opsonized A( by primary microglia will be measured in the presence and absence of lovastatin. Additionally we will examine putative reductions in AD-like pathology following lovastatin treatment Tg2576 mice treated with both lovastatin and an agonist mouse CD40 antibody. Finally additive or synergistic therapeutic effects are expected to occur when lovastatin is co-administered with A( vaccine and this will be tested by comparing A( vaccinated and PBS immunized Tg2576 mice treated with lovastatin or control and sacrificed at several ages. PUBLIC HEALTH RELEVANCE: Project Narrative Alzheimer's disease (AD) is a chronic, progressive dementia associated with impairment in memory and behavior. It currently accounts for about 70% of all dementias and onset typically occurs in mid-late life. The frequency doubles every five years after age 60, increasing from a prevalence of about 1% in individuals aged 60 years to about 40% among those aged 85 years or greater. Thus this disease is a clear healthcare problem for both veterans and all individuals living past the age of 60. Furthermore, as the aging population grows, AD will become an even greater socioeconomic problem. Indeed AD prevalence is expected to rise dramatically through the mid 21st century, concurrently with various conflicts in the Middle East. It is projected the number of AD patients in the U.S.A. will rise to 13.2 million by that time, not accounting for U.S. forces deployed oversees. In terms of VA healthcare costs, it was estimated that the total direct and indirect costs related to AD alone are, on a per-patient basis, some $91,000 over the course the illness. The major brain abnormality in AD is thought is to be the presence of extracellular senile plaques in the brain primarily composed of amyloid beta (A() peptides. Strategies targeting the clearance of these plaques from the brain may help patients suffering from AD. We have experience with two such strategies in mouse models. One is vaccination with the A( peptide. We found this decreased senile plaques in AD mouse models while improving their memory. The second strategy is the administration of a common anti-cholesterol drug known as lovastatin. This too had similar effects as vaccination. However neither strategy alone is sufficient as recovery of the brain, and a return to normal behavior is not seen. Further, clinical trials of vaccination were halted due to serious side effects which we likely may be overcome by the addition of lovastatin. Thus, our long-term objective is to test the hypothesis that combined vaccination and lovastaitn therapy will be mutually beneficial as a co- administrated AD treatment in AD model mice. Lovastatin is predicted to abrogate the potential adverse effects of the A( vaccination by increasing anti-inflammatory chemicals in the brain and should also reduce memory problems further than vaccination alone. This will be tested by comparing behavior and brain health in several mouse groups including: A( vaccinated (alone) and those treated with lovastatin plus A( vaccination.