Statin modulation of immunotherapy for Alzheimer disease

他汀类药物调节阿尔茨海默病免疫疗法

• 批准号: 7681379
• 负责人: Jun Tan
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681379
• 关键词: Accounting; Adverse effects; Age; Agonist; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Anticholesteremic Agents; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; Behavior; Behavioral; Biochemical; Blood; Brain; Cell surface; Cerebral Amyloid Angiopathy; Cerebrum; Chemicals; Chronic; Clinical Trials; Cognition; Cognitive deficits; Conflict (Psychology); Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Dementia; Deposition; Development; Direct Costs; Disease; Elderly; Encephalitis; Excision; Facilities and Administrative Costs; Fc Receptor; Flow Cytometry; Frequencies; Future; Health; Health Care Costs; Healthcare; Immunoglobulin G; Immunosuppression; Immunotherapy; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-10; Interleukin-4; Interleukin-6; Knockout Mice; Lead; Length; Life; Ligation; Lovastatin; Measures; Mediating; Memory; Memory impairment; Microglia; Middle East; Mus; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Phagocytosis; Phenotype; Phosphorylation; Preparation; Prevalence; Production; Property; Recovery; Regulation; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; STAT1 gene; Senile Plaques; Short-Term Memory; Signal Pathway; Signal Transduction; TNFRSF5 gene; TNFSF5 gene; Testing; Tg2576; Therapeutic; Therapeutic Effect; Therapy Clinical Trials; Time; Transforming Growth Factor beta; Transgenic Mice; Tumor Necrosis Factor-alpha; Vaccinated; Vaccination; Vaccines; Validation; Veterans; Western Blotting; abstracting; aged; aging population; base; beta amyloid pathology; crosslink; cytokine; design; experience; extracellular; human TNF protein; improved; in vitro testing; in vivo; inhibitor/antagonist; mouse model; peptide A; public health relevance; response; socioeconomics; success; uptake; vaccination strategy

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.

描述（由申请人提供）： 阿尔茨海默病（AD）是老年人中最常见的痴呆性疾病，并成为主要的退伍军人健康和/或医疗保健问题。其病理特征在于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（A（1-40，42）肽组成。靶向A（斑块）的清除或A的前体可溶性或寡聚形式（其先于斑块形成）的中和的策略一直是患有AD的患者的密集研究的焦点。 一种不同的抗AD策略，用A β肽接种，也减少了AD转基因小鼠中的A β沉积并改善认知。关于A（免疫疗法）的作用的两个主要假设是通过Fc受体促进小胶质细胞吞噬作用和通过抗A（抗体外周库）增加脑/血液浓度梯度促进A（从脑中去除）。这种疗法的临床试验由于部分病例的脑部炎症而停止。尽管有这种副作用，这项试验的第一份报告表明，在减缓产生抗脑A抗体的患者痴呆症进展速度方面取得了一些成功。 我们的长期目标是测试以下假设：组合的抗A治疗（疫苗接种）和lovastaitn（抗CD 40治疗）作为共同施用的AD免疫治疗策略将是互惠的，不仅消除可能由疫苗接种引起的炎症，而且改善AD模型小鼠的记忆缺陷。预测洛伐他汀通过增加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来消除抗A免疫疗法的潜在不良作用。此外，洛伐他汀介导的CD 40信号传导的破坏应该通过极化处于吞噬状态的活化的小胶质细胞来增强A抗体的A清除特性。这些作用将在体外和体内进行测试，目的是在细胞表面、细胞因子和小胶质细胞吞噬或抗原呈递状态特异性信号传导标志物方面，充分表征CD 40连接后洛伐他汀对小胶质细胞吞噬和抗原呈递表型的调节。此外，将在存在和不存在洛伐他汀的情况下测量原代小胶质细胞对IgG调理的A β的摄取。此外，我们将检查洛伐他汀治疗后AD样病理学的推定减少，用洛伐他汀和激动剂小鼠CD 40抗体治疗的Tg 2576小鼠。最后，当洛伐他汀与A β疫苗共同给药时，预期会发生累加或协同治疗作用，这将通过比较A β疫苗接种和PBS免疫的Tg 2576小鼠来测试，Tg 2576小鼠用洛伐他汀或对照处理并在几个年龄处死。 公共卫生相关性： 阿尔茨海默病（AD）是一种慢性、进行性痴呆，伴有记忆和行为障碍。它目前约占所有痴呆症的70%，通常发生在中晚期。在60岁以后，发病率每五年翻一番，从60岁个体的约1%增加到85岁或以上个体的约40%。因此，这种疾病对于退伍军人和所有60岁以上的人来说都是一个明显的医疗保健问题。此外，随着人口老龄化的增长，AD将成为一个更大的社会经济问题。事实上，AD患病率预计将在整个世纪中期急剧上升，同时在中东发生各种冲突。预计到那时，美国的AD患者人数将增加到1320万，这还不包括部署在海外的美国军队。就VA医疗保健成本而言，据估计，仅与AD相关的直接和间接成本总额，以每位患者为基础，在疾病过程中约为91，000美元。AD的主要脑异常被认为是脑中存在主要由淀粉样β（A）肽组成的细胞外老年斑。从大脑中清除这些斑块的策略可能有助于AD患者。我们在小鼠模型中有两种这样的策略的经验。一种是用A肽接种疫苗。我们发现这减少了AD小鼠模型中的老年斑，同时改善了它们的记忆力。第二种策略是服用一种常见的抗胆固醇药物，称为洛伐他汀。这与接种疫苗的效果相似。然而，这两种策略都不足以恢复大脑，并且没有看到恢复正常行为。此外，由于严重的副作用，疫苗接种的临床试验被停止，我们可能可以通过添加洛伐他汀来克服这些副作用。因此，我们的长期目标是检验组合疫苗接种和lovastaitn疗法作为AD模型小鼠中的共同施用的AD治疗将是互利的这一假设。预计洛伐他汀可以通过增加大脑中的抗炎化学物质来消除A疫苗接种的潜在不良影响，并且还应该比单独接种疫苗进一步减少记忆问题。这将通过比较几个小鼠组的行为和大脑健康来测试，这些小鼠组包括：A（单独接种疫苗）和用洛伐他汀加A（接种疫苗）治疗的小鼠。