Statins for Alzheimer's disease immunotherapy

描述（由申请人提供）：阿尔茨海默病（AD）是60岁以后痴呆症的最常见原因。阿尔茨海默病的病理特征包括淀粉样b肽（Ab）在神经斑块和脑血管中的沉积、神经原纤维缠结和神经元的丧失。越来越多的证据支持Ab及其前体在AD发病机制中起重要作用的观点。用合成抗体免疫AD小鼠模型可防止或减少Ab沉积，改善其记忆和学习缺陷。抗体免疫（AN1792）的人体临床试验因脑部炎症而中止。此外，临床试验和被动免疫分别导致1例AD患者和部分AD小鼠模型出现脑出血。最近的临床试验报告表明，Ab免疫可有效清除AD患者的Ab沉积，改善AD患者的认知缺陷，因此寻找一种安全有效的免疫治疗方法至关重要。由于抗Ab抗体的外周给药也诱导AD小鼠模型中预先存在的淀粉样斑块的清除，并且由于与AN1792试验相关的脑膜脑炎被认为是T细胞介导的自身免疫反应，因此主要引起T辅助（Th） 2型免疫反应的免疫模式被认为对AD的预防和治疗更安全。阿尔茨海默病免疫治疗的另一个障碍是难以在阿尔茨海默病患者中诱导适当的抗ab滴度。在II期临床试验中，19.7%的AD患者出现Ab滴度阳性。在试图开发这种安全有效的疫苗的过程中，我们证明了编码Ab的腺病毒载体疫苗可以在几种小鼠中诱导th2极化的抗炎免疫反应。我们发现，与仅接种腺病毒相比，DNA启动物-腺病毒增强方案增加了抗ab抗体阳性小鼠的数量，抗体滴度值和抗体对淀粉样斑块的亲和力。因此，异源DNA引物-腺病毒增强方案优于其同源对应物。我们假设，异源DNA启动物-腺病毒增强方案可有效减少AD小鼠模型中的Ab沉积和改善行为缺陷，他汀类药物可增强DNA启动物-腺病毒增强方案诱导的th2型反应，并保护动物免受脑炎和出血。在目的1中，我们将评估DNA引物-腺病毒增强免疫在AD模型小鼠中的有效性和安全性。在ai2中，我们将评估DNA -腺病毒增强免疫与辛伐他汀联合治疗AD模型小鼠的有效性和安全性。我们将对动物进行免疫学、组织病理学、免疫组织化学、生化和行为分析，以确定该方法的有效性和安全性。本项目的目标是通过测试DNA -腺病毒增强方案与他汀类药物的联合治疗，为开发安全有效的阿尔茨海默病治疗方案建立逻辑基础。公共卫生相关性：阿尔茨海默病（AD）是老年人痴呆的最常见原因。然而，到目前为止，还没有令人满意的治疗AD的方法。这项研究将作为一个原则性的证明，证明DNA原病毒增强免疫与他汀类药物相比，可以诱导更安全、更有效的免疫反应来治疗阿尔茨海默病。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of AD include deposition of amyloid b-peptide (Ab) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles and loss of neurons. Increasing evidence supports the notion that Ab and its precursor play important roles in the pathogenesis of AD. Immunization of AD mouse models with synthetic Ab prevented or reduced Ab deposits and improved their memory and learning deficits. Human clinical trials of Ab immunization (AN1792) were halted due to brain inflammation. In addition, the clinical trials and passive immunization induced cerebral hemorrhages in one AD patient and some AD mouse models, respectively. Recent reports of the clinical trials indicate that Ab immunization is effective in clearing Ab deposits and improving cognitive deficits in AD patients Thus, it is crucial to find a safe and effective immune therapy. Because peripheral administration of antibodies against Ab also induced clearance of preexisting amyloid plaques in AD mouse models and because meningoencephalitis associated with the AN1792 trial is thought to be T-cell-mediated auto-immune responses, immunization modalities that elicit predominantly T helper (Th) type 2 immune responses are considered to be safer for AD prevention and treatment. Another obstacle for AD immunotherapy is the difficulty to induce an appropriate anti-Ab titer in AD patients. In the phase II clinical trial, 19.7% of AD patients developed a positive Ab titer. In attempting to develop such safe, effective vaccines, we demonstrated that adenovirus-vectored vaccines encoding Ab can induce Th2-polarized anti-inflammatory immune responses in several strains of mice. We found that a DNA prime-adenovirus boost regimen increased the number of mice positive for anti-Ab antibody, the value of the antibody titer and the affinity of the antibody to amyloid plaques compared with only adenovirus immunization. Thus, the heterologous DNA prime-adenovirus boost regimen is superior to its homologous counterpart. We hypothesize that a heterologous DNA prime-adenovirus boost regimen is effective in reducing Ab deposits and in improving behavioral deficits in AD mouse models and that statins enhance Th2-type responses induced by a DNA prime-adenovirus boost regimen and protect animals against brain inflammation and hemorrhages. In Aim 1, we will evaluate the efficacy and safety of DNA prime-adenovirus boost immunization in AD model mice. In Aim2, We will evaluate the efficacy and safety of combined treatment of DNA prime-adenovirus boost immunization with simvastatin in AD model mice. We will perform immunological, histopathological, immunohistochemical, biochemical and behavioral analyses on the animals to determine the efficacy and safety of the modalities. The efficacy and safety of the immunization with simvastatin will be compared with those without statins The goal of this project is to establish the logical basis for developing safe, effective modalities for AD by testing combination therapy of DNA prime-adenovirus boost regimens with statins. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. This study will serve as a proof of principle to demonstrate if DNA prime-virus boost immunization with statins can induce potentially safer and more efficacious immune responses to treat AD than that without statins.