Innate immunity in Alzheimer's disease: Role of toll-like receptor signaling

阿尔茨海默氏病的先天免疫：Toll 样受体信号传导的作用

基本信息

批准号：
7904117
负责人：
Ken-ichiro Fukuchi
金额：
$ 31.86万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904117
关键词：
Acute-Phase Proteins Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid Proteins Amyloidosis Animal Model Animals Behavioral Brain Cells Cerebrum Complement Conflict (Psychology)Dementia Dependovirus Deposition Disease Disease Progression Elderly Etiology Event Functional disorder Gene Delivery Genetic Goals Immune Immune response Immune system In Vitro Inflammation Ingestion Interleukin-10 Interleukin-17 Interleukin-6 Ligands Lipopolysaccharides Mediating Microglia Modality Molecular Profiling Mouse Cell Line Mouse Strains Mus Mutation Myelogenous Names Natural Immunity Nerve Degeneration Neuraxis Partner in relationship Pathology Pathway interactions Patients Pattern recognition receptor Peptide Hydrolases Phagocytes Play Proteins Receptor Signaling Recombinant adeno-associated virus (rAAV)Research Role Senile Plaques Signal Transduction Signaling Molecule Staging TLR4 gene Testing Tissue Sample Tissues Toll-like receptor 6 Toll-like receptors Transgenic Mice Up-Regulation cerebrovascular chemokine cognitive function congenic cytokine cytotoxic gene therapy improved in vivo lipoteichoic acid mouse model mutant novel overexpression pathogen prevent public health relevance receptor response wasting

项目摘要

DESCRIPTION (provided by applicant): Patients with Alzheimer's disease (AD) develop deposits of aggregated amyloid ¿-protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. Fibrillar A2 deposits in AD brain are accompanied by innate immune responses such as activated microglia and increased levels of cytokines. Accumulating evidence supports the hypothesis that activated microglia, innate immune cells in the central nervous system, play a pivotal role in the AD progression: either clearing A¿ deposits by phagocytic activity or releasing cytotoxic substances. Toll-like receptors (TLRs) are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate phagocytes/microglia to respond to insults including pathogens and damaged host cells, leading to clearance of pathogens, damaged tissues and accumulated wastes. We hypothesize that these protective functions are mediated by MyD88-dependent pathways and that A¿ load in the brain can be modulated by TLR4 signaling. We will determine the roles of MyD88-dependent pathways and TLR4 signaling in A¿ clearance by completing the Specific Aim 1 and 2. We further hypothesize that A¿ load in the brain and cognitive functions are modulated by TLR4 effector cytokines/chemokines, which will be tested by performing Aim 3. In Aim 4, we will test the hypothesis that accumulation of A¿ in the brain induces dysfunction of TLR4 signaling in microglia resulting in exacerbation of A¿ deposition in AD patients and AD mouse models. Specific Aims are (Aim 1) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models on a MyD88-deficient genetic background, (Aim 2) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models that overexpress TLR4, (Aim 3a) to compare cerebral cytokine and chemokine expression profiles between TLR4 wild-type and mutant AD mouse models, (Aim 3b) to overexpress TLR4 effector cytokines and/or chemokines in the brain via adeno-associated virus gene delivery and determine cerebral A¿ load, inflammation and behavioral deficits in the AD mouse models, and (Aim 4) to determine whether A¿ induces dysfunction of TLR signaling, using cultured microglia, AD mouse models and tissue samples from AD patients. The long term goal of this research is to determine the roles of TLR signaling and its effector cytokines/chemokines in the AD progression. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. Patients with AD develop deposits of aggregated amyloid 2 protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. This study will elucidate the mechanisms by which A¿ deposits are cleared and serve as a proof of principle to demonstrate if our novel cytokine/chemokine gene therapy modality is effective in treating an animal model of AD.