Statins for Alzheimer's disease immunotherapy

描述（由申请人提供）：阿尔茨海默病（AD）是60岁后痴呆症的最常见原因。AD的病理学特征包括神经炎性斑块和脑血管中淀粉样蛋白B肽（Ab）的沉积、神经元缠结和神经元丢失。越来越多的证据支持Ab及其前体在AD的发病机制中起重要作用的观点。用合成Ab免疫AD小鼠模型预防或减少Ab沉积并改善其记忆和学习缺陷。Ab免疫的人类临床试验（AN 1792）由于脑炎症而停止。此外，临床试验和被动免疫分别在一名AD患者和一些AD小鼠模型中诱导脑损伤。近年来的临床研究表明，Ab免疫可有效清除Ab沉积，改善AD患者的认知功能，因此寻找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小鼠模型中既存淀粉样蛋白斑块的清除，并且由于与AN 1792试验相关的脑膜脑炎被认为是T细胞介导的自身免疫应答，因此认为主要引发辅助性T细胞（Th）2型免疫应答的免疫方式对于AD预防和治疗更安全。AD免疫治疗的另一个障碍是难以在AD患者中诱导适当的抗Ab滴度。在II期临床试验中，19.7%的AD患者出现抗体滴度阳性。在试图开发这种安全、有效的疫苗时，我们证明了编码Ab的腺病毒载体疫苗可以在几种小鼠品系中诱导Th 2极化的抗炎免疫应答。我们发现，与仅腺病毒免疫相比，DNA引发-腺病毒加强方案增加了抗Ab抗体阳性小鼠的数量、抗体滴度的值和抗体对淀粉样蛋白斑块的亲和力。因此，异源DNA初免-腺病毒加强方案上级其同源对应物。我们假设异源DNA引发-腺病毒加强方案在减少Ab沉积和改善AD小鼠模型中的行为缺陷方面是有效的，并且他汀类药物增强DNA引发-腺病毒加强方案诱导的Th 2型应答并保护动物免受脑炎症和脑损伤。目的一：评价DNA初免-腺病毒加强免疫治疗AD模型小鼠的有效性和安全性。目的2：评价辛伐他汀联合DNA初免-腺病毒加强免疫治疗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、生物化学和行为分析，以确定这些方法的有效性和安全性。本项目的目的是通过检测DNA初免-腺病毒加强免疫方案与他汀类药物的联合治疗，为开发安全、有效的AD治疗模式奠定逻辑基础。公共卫生相关性：阿尔茨海默病（AD）是老年痴呆症最常见的原因。然而，迄今为止，没有令人满意的治疗AD。这项研究将作为一个原则的证据，以证明如果DNA引发病毒加强免疫与他汀类药物可以诱导潜在的更安全和更有效的免疫反应，以治疗AD比没有他汀类药物。

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.