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：
8649898
负责人：
David Gate
金额：
$ 3.58万
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/8649898
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 Peptides 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 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.

项目概要/摘要阿尔茨海默病 (AD) 是最常见的痴呆症，其特点是 A¿ 沉积肽如 '老年' ¿ -淀粉样斑块、神经病理学和神经炎症是种系的-。先天免疫系统细胞编码病原体传感器，并在淀粉样蛋白中发挥不同作用 TLR 通过丝氨酸/苏氨酸 IL-1 受体相关激酶转导信号。 (IRAK)。IRAK 家族主要由正向调节 TLR 信号传导的激酶组成，其中值得注意的是。除抑制性激酶外，IRAK-M 表达对单核细胞谱系具有特异性，包括小胶质细胞，并在控制先天免疫反应方面发挥着关键作用。 IRAK-M 参与脑淀粉样蛋白重塑，我们将缺乏 IRAK-M (IRAK-M-/-) 的小鼠与过度表达突变型人类淀粉样前体蛋白的小鼠，APPPS1 小鼠脑模型然后我们评估了免疫细胞激活和脑淀粉样变性的状态。年龄和性别的负担来自三组的匹配同窝小鼠：APPPS1-IRAK-M+/+、APPPS1-IRAK-M-/+ 和 APPPS1-IRAK-M-/- 小鼠。初步数据显示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，脑实质 A¿ APPPS1-中的丰度相应减弱通过生化方法对 APPPS1- 进行共聚焦成像测量的 IRAK-M-/- 小鼠。 IRAK-M-/- 小鼠大脑揭示了 A¿与溶酶体标记 LAMP1 共定位，表明 IRAK-M-/- 小胶质细胞介导的 A¿ 的吞噬机制本提案旨在测试。 IRAK-M 的去抑制是否影响淀粉样蛋白病理学的小胶质细胞重塑。 1将进一步表征IRAK-M缺陷型阿尔茨海默小鼠的大脑病理学和动物行为。拟议的实验将阐明 IRAK-M 缺陷对小胶质细胞对阿尔茨海默病反应的影响像病理学一样，包括其对认知障碍的影响，然后我们将评估细胞因子/趋化因子。体内反应以确定 IRAK-M 缺乏是否促进促炎或抗炎反应 APPPS1-IRAK-M-/- 小鼠中的小胶质细胞特定目标 2 将进一步评估 A¿在 APPPS1-IRAK- M-/- 小胶质细胞并确定 A¿ 中 IRAK-M 的功能申请人是三年级博士生。 Terrence Town 博士实验室的学生，他多年来一直从事 AD 先天免疫学领域的工作过去17年提出的培训计划概述了一套科学的职业发展活动。研讨会——例如神经病理学、动物行为和资助写作方面的高级教育——以促进完成这项工作。