Targeting Abeta phagocytosis by blocking IRAK-M innate immunity in Alzheimer mice

通过阻断阿尔茨海默病小鼠的 IRAK-M 先天免疫来靶向 Abeta 吞噬作用

基本信息

批准号：
8760213
负责人：
David Gate
金额：
$ 3.63万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2015-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760213
关键词：
Ablation Affect Age Alleles Alzheimer like pathology Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Amyloidosis Animal Behavior Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Attenuated Behavioral Assay Biochemical Biological Assay Biological Models Brain Brain Pathology Cells Centrifugation Cerebrum Chronic Complex Conflict (Psychology)Confocal Microscopy Data Dementia Deposition Disease Disinhibition Dissociation Dose Education Educational workshop Enzyme-Linked Immunosorbent Assay Event Family Fluorescein Genes Genetic Goals Grant Homeostasis Human Human Genetics Image Immune Immune Cell Activation Immune response Immune system Immunohistochemistry Immunology Impaired cognition In Vitro Inflammatory Inflammatory Response Interleukin-1 Label Laboratories Lysosomes Measurement Measures Mediating Methods Microglia Molecular Mus Mutation Natural Immunity Neuraxis Neurodegenerative Disorders Pathogenesis Pathology Pb clearance Phagocytes Phagocytosis Phosphotransferases Physiologic pulse Play Presenile Alzheimer Dementia Process Production Public Health Reaction Receptor Signaling Reporting Role Senile Plaques Serine Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA TNF receptor-associated factor 6 Testing Threonine TimeLine Toll-like receptor 6 Toll-like receptors Training Transgenic Mice Western Blotting Wild Type Mouse Work Writing amyloid pathology career development chemokine cognitive function cytokine design doctoral student improved in vivo insight macrophage monocyte morris water maze mouse model mutant neurofibrillary tangle formation neuroinflammation neuropathology novel object recognition offspring pathogen peptide A presenilin-1 presenilin-2 prevent public health relevance receptor research study response screening sensor sex tau Proteins

项目摘要

Project Summary/Abstract Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of A¿ peptides as 'senile' ¿-amyloid plaques, neuropathology, and neuroinflammation. Toll-like receptors (TLRs) are germline- encoded sensors of pathogens by cells of the innate immune system and play differential roles in amyloid homeostasis. TLRs transduce their signals through the serine/threonine IL-1 receptor-associated kinase (IRAK). The IRAK family is chiefly comprised of kinases that positively regulate TLR signaling, with the notable exception of the inhibitory kinase, IRAK-M. IRAK-M expression is specific to cells of monocytic lineage, including microglia, and plays a critical role in keeping innate immune responses in check. To test whether IRAK-M participated in cerebral amyloid remodeling, we crossed mice deficient in IRAK-M (IRAK-M-/-) with mice over expressing mutant human amyloid precursor protein, the APPPS1 mouse model of cerebral amyloidosis. We then evaluated the state of immune cell activation and cerebral A¿ burden in age and sex- matched littermates from three groups: APPPS1-IRAK-M+/+, APPPS1-IRAK-M-/+, and APPPS1-IRAK-M-/- mice. Preliminary data showed a gene dose-dependent effect where microglial activation inversely correlated with IRAK-M allele number. Further, brain parenchymal A¿ abundance was correspondingly attenuated in APPPS1- IRAK-M-/- mice as measured by biochemical approaches. Interestingly, confocal imaging of APPPS1- IRAK-M-/- mouse brains revealed A¿ colocalization with the lysosomal marker LAMP1, suggesting a phagocytic mechanism of IRAK-M-/- microglia-mediated A¿ clearance. This proposal is designed to test whether disinhibition of IRAK-M affects microglial remodeling of amyloid pathology. The focus of Specific Aim 1 will be to further characterize brain pathology and animal behavior in IRAK-M deficient Alzheimer mice. The proposed experiments will elucidate the impact of IRAK-M deficiency on the microglial response to Alzheimer- like pathology, including its influence on cognitive impairment. We will then evaluate cytokine/chemokine responses in vivo to determine the whether IRAK-M deficiency promotes pro- or anti-inflammatory reactions of microglia in APPPS1-IRAK-M-/- mice. Specific Aim 2 will further assess phagocytosis of A¿ in APPPS1-IRAK- M-/- microglia and determine the function of IRAK-M in A¿ phagocytosis. The applicant is a third-year doctoral student in the laboratory of Dr. Terrence Town, who has been working in the field of AD innate immunology for the past 17 years. The proposed training plan outlines a set of career development activities and scientific workshops - e.g. advanced education in neuropathology, animal behavior and grant writing - to facilitate completion of this work.

项目摘要/摘要阿尔茨海默氏病（AD）是最常见的痴呆症，并以A肽的沉积为标志 “老年” - 淀粉样斑块，神经病理学和神经炎症。 Toll样受体（TLR）是种系通过先天免疫系统细胞编码的病原体传感器，并在淀粉样蛋白中起鉴别作用稳态。 TLR通过丝氨酸/苏氨酸IL-1受体相关激酶转导信号（irak）。 Irak家族主要积累了激酶，它们以著名的抑制性激酶除外。 IRAK-M表达特定于单核细胞谱系的细胞，包括小胶质细胞在内，并且在控制先天免疫反应中起着至关重要的作用。测试是否 Irak-M参加了脑淀粉样蛋白的重塑，我们将缺乏IRAK-M（IRAK-M - / - ）的小鼠与小鼠超过表达突变的人淀粉样蛋白前体蛋白，脑的AppPS1小鼠模型淀粉样变性。然后，我们评估了免疫细胞激活状态和年龄和性别负担匹配三个组的同窝室：appps1-irak-m+/+，appps1-irak-m - /+和appps1-irak-m - / - 小鼠。初步数据显示了基因剂量依赖性效应，其中小胶质细胞激活与 irak-m等位基因编号。此外，在AppPS1- 通过生化方法测量的IRAK-M - / - 小鼠。有趣的是，AppPS1-的共聚焦成像 - irak-M - / - 小鼠大脑显示与溶酶体标记LAMP1共定位，这表明 irak-M - / - 小胶质细胞介导的清除率的吞噬机制。该建议旨在测试 IRAK-M的抑制是否会影响淀粉样病理学的小胶质重塑。特定目标的重点 1将进一步表征IRAK-M缺乏阿尔茨海默氏症小鼠中的脑病理学和动物行为。这提出的实验将阐明Irak-M缺乏对小胶质细胞对阿尔茨海默氏症的影响的影响就像病理一样，包括对认知障碍的影响。然后，我们将评估细胞因子/趋化因子体内反应以确定IRAK-M缺乏症是否促进了促或抗炎反应 Appps1-irak-M - / - 小鼠中的小胶质细胞。具体目标2将进一步评估Appps1-irak-中A的吞噬作用 M - / - 小胶质细胞，并确定IRAK-M在吞噬作用中的功能。申请人是三年级的博士 Terrence Town博士实验室的学生，他一直在AD先天免疫学领域工作过去17年。拟议的培训计划概述了一系列职业发展活动和科学讲习班 - 例如神经病理学，动物行为和赠款写作的高级教育 - 促进完成这项工作。