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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.

项目总结/文摘