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Anti-inflammatory regulation of beta-amyloidosis

β-淀粉样变性的抗炎调节

基本信息

批准号：
8134149
负责人：
Tsuneya Ikezu
金额：
$ 5.82万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134149
关键词：
Address Affect Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acid Sequence Amyloid beta-Protein Precursor Amyloidosis Animal Model Anti-Inflammatory Agents Anti-inflammatory Astrocytes Biology Brain CCL2 gene CD 200 Chronic Complement Core Facility Dendritic Cells Dependovirus Deposition Disease Outcome Disease Progression Dose Effectiveness Environment Experimental Designs Functional disorder Funding Gene Delivery Gene Expression Genetically Engineered Mouse Goals Head Hippocampus (Brain)IL10 gene ITGAM gene ITGAX gene Immunization Immunotherapy Impaired cognition Inflammation Inflammatory Injection of therapeutic agent Interdisciplinary Study Interferons Interleukin-10 Interleukin-4 Investigation Journals Knowledge Laboratories Left Link Mediating Medical center Memory Memory impairment Microglia Mus Nebraska Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Pathology Pharmaceutical Preparations Phenotype Play Positioning Attribute Production Proteins Proteomics Publications Recombinant adeno-associated virus (rAAV)Regulation Research Personnel Rodent Model Role Senile Plaques Signal Transduction Staging System Testing Therapeutic Transforming Growth Factors Transgenic Animals Transgenic Mice Treatment Efficacy Tumor Necrosis Factor-alpha Tumor Necrosis Factors Universities Vaccination Water Work amyloid peptide base bioimaging chemokine cognitive function copolymer 1 cytokine effective therapy familial Alzheimer disease gene delivery system improved in vivo mouse model mutant nervous system disorder neurochemistry neurogenesis neuroimmunology neuroinflammation neurophysiology neurotoxicology neurotrophic factor postsynaptic presenilin presenilin-1 presynaptic programs promoter public health relevance response synaptogenesis type I interferon receptor

项目摘要

DESCRIPTION (provided by applicant): The over-arching goal of this project is to determine the regulatory role of anti-inflammatory molecules on neuroinflammatory activities and beta-amyloidosis (A¿ aggregation and deposition in brain) in rodent models of Alzheimer's disease (AD). Our previous studies on a double transgenic mouse expressing familial AD mutants of ¿-amyloid precursor protein (APP) and glial fibrillar acidic protein promoter-driven murine CCL2 and APP transgenic mice lacking interferon-? receptor type I demonstrated that chemokines and pro-inflammatory cytokines are critically involved in progression of beta-amyloidosis and microgliosis in brain. Accordingly, glatiramer acetate immunization, a known anti-inflammatory therapy, reduced beta-amyloidosis, enhanced neurogenesis, and improved cognitive function in APP mice. In addition, specific anti-inflammatory cytokines (interleukin-4; IL-4, IL-10, among others) can directly induce anti-inflammatory and neuroprotective phenotype of microglia. Thus, we hypothesize that anti-inflammatory cytokines (IL-4 or IL-10, among others) may induce suppression of neuroinflammation and beta-amyloidosis-related cognitive dysfunction in vivo. Our preliminary studies support this hypothesis, since chronic expression of neutralizing CCL2 mutant (7ND, lacking the first 7 amino acid sequence) suppresses microgliosis and A¿ oligomer accumulation, and improves cognitive function in a double transgenic mice (APP/PS1) expressing APP and presenilin-1 (PS1). Using adeno-associated virus (AAV)-mediated gene delivery system for expressing IL-4, IL-10, 7ND in APP/PS1 mice at pre- and post- symptomatic stages of memory dysfunction, we will ask the following questions: 1) Does 7ND, IL-4, or IL-10 suppress astro/microgliosis? If so, is it restricted to hippocampal region or both in cortex and hippocampus?; 2) Does IL-4 or IL-10 induce dendritic-like (CD11c+) microglia? If so, is it neuroprotective?; 3) Does IL-4 or IL- 10 induce inflammation regulatory molecules (CD200, CD200R)?; 4) Does IL-4 or IL-10 reduce beta- amyloidosis? If so, is it specific to compact plaques, diffuse plaques, or A¿ oligomers?; 5) Does IL-4 or IL-10 enhance neurogenesis? If so, is it accompanied with enhanced newly synthesized neurons or astrocytes? 6) Does IL-4 or IL-10 enhance synaptogenesis? If so, is it specific to presynaptic or postsynaptic molecules?; and 7) Does 7ND, IL-4 or IL-10 enhance memory formation after injection of lower doses of AAV? If so, is it effective in both pre-symptomatic and post-symptomatic stages? This proposal is significant, since to the best of our knowledge, therapeutic efficacy of 7ND, IL-4 or IL-10 gene delivery has never been tested in APP or APP/PS1 mice in vivo. These approaches may have significant implication for immunotherapy of AD and other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a leading neurological disease that affects more than 4 million people in the US, who are left without effective therapy. Using the established the genetically engineered mouse model of AD (APP/PS1 mice), we will characterize the beneficial effect of anti-inflammatory cytokines (interleukin-4 and 10) and neutralizing chemokine mutant (for CCL2), on beta-amyloidosis and cognitive function inAPP/PS1 mice. These approaches may have therapeutic implication for AD and other neurodegenerative diseases.

描述（由申请人提供）：本项目的主要目标是确定抗炎分子对阿尔茨海默病（AD）啮齿动物模型中神经炎症活动和β-淀粉样变性（A？聚集和沉积）的调节作用。我们以前的研究双转基因小鼠表达家族性AD突变体的淀粉样前体蛋白（APP）和胶质纤维酸性蛋白启动子驱动的小鼠CCL 2和APP转基因小鼠缺乏干扰素？I型受体证实趋化因子和促炎细胞因子在脑中β-淀粉样变性和小神经胶质增生的进展中起关键作用。因此，醋酸格拉替雷免疫，一种已知的抗炎疗法，减少了β-淀粉样变性，增强了神经发生，并改善了APP小鼠的认知功能。此外，特异性抗炎细胞因子（白细胞介素-4; IL-4、IL-10等）可以直接诱导小胶质细胞的抗炎和神经保护表型。因此，我们假设抗炎细胞因子（IL-4或IL-10等）可能诱导抑制体内神经炎症和β-淀粉样变性相关的认知功能障碍。我们的初步研究支持这一假设，因为慢性表达的中和CCL 2突变体（7 ND，缺乏前7个氨基酸序列）抑制小胶质细胞增生和A？寡聚体积累，并改善认知功能的双转基因小鼠（APP/PS1）表达APP和早老素-1（PS1）。利用腺相关病毒（AAV）介导的基因递送系统在APP/PS1小鼠中表达IL-4、IL-10、7 ND，在记忆功能障碍的症状前和症状后阶段，我们将提出以下问题：1）7 ND、IL-4或IL-10是否抑制星形/小胶质细胞增生？如果是，它是局限于海马区还是同时存在于皮层和海马区？2)IL-4或IL-10是否诱导树突样（CD 11 c+）小胶质细胞？如果是，它有神经保护作用吗？3)IL-4或IL- 10是否诱导炎症调节分子（CD 200、CD 200 R）？4)IL-4或IL-10能减轻β淀粉样变性吗？如果是，它是特异于致密斑块、弥散斑块还是A？寡聚体？5)IL-4或IL-10能促进神经发生吗？如果是这样，它是否伴随着增强的新合成的神经元或星形胶质细胞？6)IL-4或IL-10能促进突触发生吗？如果是，它是突触前还是突触后分子特有的？和7）7 ND、IL-4或IL-10是否在注射低剂量AAV后增强记忆形成？如果是，它在症状前和症状后阶段都有效吗？这一提议是重要的，因为据我们所知，7 ND、IL-4或IL-10基因递送的治疗功效从未在APP或APP/PS1小鼠体内测试过。这些方法可能对AD和其他神经退行性疾病的免疫治疗具有重要意义。公共卫生相关性：阿尔茨海默病（AD）是一种主要的神经系统疾病，在美国影响超过400万人，他们没有有效的治疗。本研究利用已建立的AD基因工程小鼠模型（APP/PS1小鼠），研究抗炎细胞因子（白细胞介素-4和10）和中和性趋化因子突变体（CCL 2）对APP/PS1小鼠β-淀粉样变性和认知功能的影响。这些方法可能对AD和其他神经退行性疾病具有治疗意义。