权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Toll-Like Receptor Signaling in Alzheimer's Disease

阿尔茨海默病中的 Toll 样受体信号转导

基本信息

批准号：
8679097
负责人：
JOSEPH EL EL-KHOURY
金额：
$ 16.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2013-09-13 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8679097
关键词：
Adaptor Signaling Protein Alzheimer&apos s Disease Amyloid Amyloid deposition Amyloidosis Astrocytes Atherosclerosis Binding Brain CD14 gene CD36 gene Cells Cerebrum Chronic Complement Complex Data Deposition Development Disease Disease Progression Family Generations Genes Goals Host Defense Immune Immune response Immune system In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Invaded Laboratories Ligands Ligation Measures Mediating Microglia Molecular Molecular Structure Mus Nerve Degeneration Neurons Nitrogen Oxygen Pathogenesis Pathology Pathway interactions Pattern recognition receptor Phagocytosis Production Proteins Rage Receptor Signaling Role Senile Plaques Signal Pathway Signal Transduction Site Sterility Syndrome System TLR4 gene TLR6 gene Testing Toll-like receptors amyloid peptide base brain cell chemokine cytokine enzyme activity in vivo inflammatory marker insight microbial neurotoxic neurotoxicity pathogen receptor receptor binding response scavenger receptor secretase therapeutic target

项目摘要

Microglia are the principal innate immune cells of the brain. In Alzheimer's disease (AD) these cells bind B-amyloid (AB) and accumulate at sites of AB deposition, including senile plaques. Microglial interactions with AB promote a chronic inflammatory response characterized by the production of pro-inflammatory cytokines and chemokines, reactive oxygen and nitrogen species, and complement proteins. This sterile inflammation is maintained by persistent microglial activation by AB and leads to neuronal degeneration and increased AB deposition and therefore promotes disease progression. The receptors that bind AB and the signaling pathways triggered by AB that promote chronic inflammation are not fully understood. Our long-term goals are to identify the molecular mechanisms of microglial activation by AB and the impact of these pathways on AD pathogenesis. We hypothesize that Toll-like receptors (TLR), an evolutionarily ancient family of pattern recognition receptors that detect microbial ligands, initiate and maintain the microglial inflammatory response to AB . This hypothesis is based on preliminary findings that targeted deletion of the TLR signaling adaptor MyD88 abrogates microglial inflammatory responses to AB in vitro and in vivo. In this proposal, we will define the TLRs and co-receptors responsible for initiating this signaling, their impact on microglial inflammatory responses and the implications for disease. Specifically, we will (1) Define the role of TLR ligation and signaling on microglial responses to AB in vitro, (2) Determine the role of AB co-receptors in facilitating TLR signaling, and (3) Determine the impact of AB -TLR signaling on Alzheimer's disease pathology in vivo. Understanding the mechanism(s) of microglial interactions with AB and identifying the receptors involved in these interactions will provide valuable insight into the role of these cells in the pathogenesis of AD and potentially identify therapeutic targets in AD to promote microglial clearance of AB while downregulating their neurotoxic effects.

小胶质细胞是大脑中主要的先天免疫细胞。在阿尔茨海默病（AD）中，这些细胞结合b -淀粉样蛋白（AB）并积聚在AB沉积的部位，包括老年斑。小胶质细胞与AB的相互作用促进慢性炎症反应，其特征是产生促炎细胞因子和趋化因子、活性氧和活性氮以及补体蛋白。这种无菌炎症通过AB持续激活小胶质细胞来维持，并导致神经元变性和AB沉积增加，从而促进疾病进展。结合AB的受体和AB引发的促进慢性炎症的信号通路尚不完全清楚。我们的长期目标是确定AB激活小胶质细胞的分子机制以及这些途径对AD发病机制的影响。我们假设toll样受体（TLR），一个进化上古老的模式识别受体家族，检测微生物配体，启动并维持小胶质细胞对AB的炎症反应。这一假设是基于初步发现，靶向删除TLR信号接头MyD88可以消除体外和体内小胶质细胞对AB的炎症反应。在本提案中，我们将定义负责启动该信号的tlr和共受体，它们对小胶质细胞炎症反应的影响及其对疾病的影响。具体而言，我们将(1)确定TLR连接和信号传导在体外小胶质细胞对AB的反应中的作用，(2)确定AB共受体在促进TLR信号传导中的作用，以及(3)确定AB -TLR信号传导在体内阿尔茨海默病病理中的影响。了解小胶质细胞与AB相互作用的机制，并确定参与这些相互作用的受体，将为这些细胞在AD发病机制中的作用提供有价值的见解，并有可能确定AD的治疗靶点，以促进AB的小胶质细胞清除，同时下调其神经毒性作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

β-amyloid, microglia, and the inflammasome in Alzheimer's disease.

DOI：
10.1007/s00281-015-0518-0
发表时间：
2015-11
期刊：
Seminars in immunopathology
影响因子：
9
作者：
Gold M;El Khoury J
通讯作者：
El Khoury J

Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease.

DOI：
10.1155/2012/489456
发表时间：
2012
期刊：
International journal of Alzheimer's disease
影响因子：
0
作者：
Wilkinson K;El Khoury J
通讯作者：
El Khoury J

TREM2 and the neuroimmunology of Alzheimer's disease.

DOI：
10.1016/j.bcp.2013.11.021
发表时间：
2014-04-15
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Hickman, Suzanne E.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph

The role of TLR4 896 A>G and 1196 C>T in susceptibility to infections: a review and meta-analysis of genetic association studies.

TLR4 896 A>G 和 1196 C>T 在感染易感性中的作用：遗传关联研究的回顾和荟萃分析。

DOI：
10.1371/journal.pone.0081047
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Ziakas,PanayiotisD;Prodromou,MichaelL;ElKhoury,Joseph;Zintzaras,Elias;Mylonakis,Eleftherios
通讯作者：
Mylonakis,Eleftherios

The microglial sensome revealed by direct RNA sequencing.

DOI：
10.1038/nn.3554
发表时间：
2013-12
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
Hickman, Suzanne E.;Kingery, Nathan D.;Ohsumi, Toshiro K.;Borowsky, Mark L.;Wang, Li-chong;Means, Terry K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph