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）： 阿尔茨海默氏病摘要/摘要阿尔茨海默氏病（AD）的分他汀类药物调节是老年人中最常见的痴呆症疾病，成为老兵的健康和/或医疗保健问题。在病理上，它的特征是大脑中存在细胞外质斑块，主要由40-42氨基酸长度淀粉样蛋白β（A（1-40，42）肽组成。或A的寡聚形式（在牙菌斑形成之前一直是患有AD患者的强烈研究的焦点。一种不同的抗AD策略，使用A（肽，也降低了AD转基因小鼠的沉积并改善认知的疫苗）。关于A的作用的两个主要假设（免疫疗法是通过FC受体促进小胶质细胞吞噬作用，并促进A（通过通过抗A增加大脑/血液浓度梯度从大脑中促进抗体（抗体外周血水槽）。该疗法的临床试验。由于病例的子集中的脑部炎症而被停止，尽管这一副作用，该试验表明，在降低了针对脑的抗体的痴呆症进展速度方面有所成功。 我们的长期目标是检验抗A（治疗（疫苗接种）和lovastaitn（抗CD40治疗）的合并假设，将是互惠互利的，这是一种共同给药的AD免疫疗法策略，不仅消除了可能由疫苗接种而导致的炎症，但在改善AD模型小鼠的记忆缺陷方面，可以预测可消除抗A的潜在不良反应（通过增加大脑中的抗炎细胞因子的免疫疗法，并减慢小胶质细胞的成熟促炎性抗原表现出表型。旨在完全表征CD40结扎后的小胶质细胞和抗原表型的lovastatin调节，以细胞表面，细胞因子和特定于吞噬或抗原呈现小胶质细胞状态的信号标志物来调节。此外，IgG揭露的A的摄取（将通过原发性小胶质细胞在存在和不存在lodastatin的情况下测量。此外，我们将检查洛伐他汀治疗TG2576小鼠在用lovastin和lovastatin和a lovastatin和a anistist小鼠CD40抗体治疗后的AD样病理学的推定降低。最终，当lovastatin与A共同管理（疫苗，这将通过比较A进行测试）（疫苗接种和PBS免疫的TG2576小鼠，用lovastatin或对照处理并在几个年龄牺牲时，预计将进行添加剂或协同的治疗作用。 公共卫生相关性： 阿尔茨海默氏病项目叙事（AD）是一种与记忆和行为障碍相关的慢性，进行性痴呆。目前，它约占所有痴呆症的70％，并且发作通常发生在中期生活中。 60岁以后的频率每五年增加一倍，从60岁的个体的患病率增加到85岁或更高的人的40％。因此，这种疾病对于退伍军人和60岁以上的所有人来说都是一个明显的医疗问题。此外，随着人口衰老的增长，AD将成为更大的社会经济问题。实际上，AD患病率预计在21世纪中叶会急剧上升，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1,320万，而不是对部署的美国部队负责。就VA医疗保健费用而言，据估计，与AD相关的总直接和间接成本在每个患者的情况下约为91,000美元。 AD中的主要大脑异常被认为是主要由淀粉样蛋白β组成的大脑中细胞外老年斑块的存在（a（）肽。针对大脑清除这些斑块的策略可能会帮助患有AD的患者。在小鼠模型中具有两种此类策略的经验。这也与疫苗接种相似。因此，lovastatin的增加。洛伐他汀预计将消除A（通过增加大脑中抗炎化学物质的疫苗接种的潜在不良影响，并且还应仅仅与仅疫苗接种相比。 A（接种疫苗（单独）和接受lovastatin和A（疫苗接种）治疗的人。