Functional Interaction of Amyloid-b Protein with Glial Toll-Like Receptors

淀粉样蛋白-b 与神经胶质 Toll 样受体的功能相互作用

• 批准号: 8101760
• 负责人: Michael R. Nichols
• 金额: $ 36.31万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101760
• 关键词: Academic Research Enhancement Awards; Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Antibodies; Area; Astrocytes; Beryllium; Biochemical; Biochemistry; Biological; Biophysics; Brain; Cell Surface Receptors; Cell surface; Cells; Cellular biology; Cessation of life; Complex; Cytopathology; Data; Dementia; Deposition; Detection; Diffuse; Disease; Disease Progression; Elements; Faculty; Future; Heart Diseases; Human; Immune; Immune response; Immune system; Indium; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Knockout Mice; Knowledge; Laboratories; Learning; Link; Malignant neoplasm of prostate; Mediating; Medical; Microglia; Microscopy; Mission; Molecular; Molecular Conformation; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Peptides; Play; Process; Production; Property; Proteins; Public Health; Publishing; Receptor Signaling; Relative (related person); Research; Research Personnel; Research Training; Resources; Role; Science; Senile Plaques; Signal Transduction; Spectrum Analysis; Staining method; Stains; Sterility; Stroke; Structure; Students; Techniques; Therapeutic; Time; Toll-like receptors; Training; Transgenic Organisms; Work; base; cofactor; cytokine; design; fighting; in vivo; inflammatory marker; light scattering; macromolecule; malignant breast neoplasm; microbial; nanoscience; neuron loss; prevent; progressive neurodegeneration; protein structure; receptor; relating to nervous system; response; skills; tau aggregation

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative illness characterized by increasing dementia and ultimately death. Outstanding pathological features of AD include severe neuronal loss, accumulation of aggregated amyloid-¿ protein (A¿) in senile plaques and diffuse deposits, and neurofibrillary tau tangles. It is generally agreed that A¿ accumulation is a primary cause of AD yet several central questions remain. 1) What A¿ structure, aggregation state or species contributes to AD? and 2) How does the human immune system recognize and respond to A¿? Significant data demonstrate a sustained inflammatory response to A¿ in the AD brain which includes clustering of activated microglia and cytokines around A¿ deposits. Surprisingly, not all A¿ deposits provoke an inflammatory response suggesting that A¿ morphology/structure influences the response. These results raise several puzzling questions regarding the mechanism by which A¿ provokes an inflammatory response. Recent work has established that Toll-like receptors (TLRs) of the innate immune system mediate a proinflammatory response to aggregated A¿ suggesting that A¿ may possess structural elements that are similar to microbial macromolecules. The work in this proposal will utilize biophysical and cellular studies to establish a connection between A¿ morphology/structure and inflammation in primary murine microglia and astrocytes. The first research aim will investigate a variety of conditions that influence A¿ aggregation and structure and identify the conditions that result in the greatest A¿ proinflammatory activity (cytokine production) in primary microglia and astrocytes. A variety of biophysical techniques will be used to further understand the connection between A¿ structure and glial activation. The second research aim will utilize normal and transgenic knockout mice to identify and characterize complexes of TLRs, co-receptors, and protein cofactors that mediate A¿ bioactivity at the glial cell surface and inside the cell. Further understanding of A¿ activity may help explain why the human immune system is ineffective at controlling AD and provide a legitimate point of therapeutic mitigation. The scientific and biomedical importance of this project is its direct contribution to the understanding of Alzheimer's disease. The additional and equally important aspect of the project is the training opportunities that it provides for graduate and undergraduate researchers. The proposed research, which is a blend of cell biology, biochemistry, biophysics, nanoscience, and spectroscopy, will attract a diverse group of students to participate in interdisciplinary studies. This broad range of science will promote collaborative work and interactions between students and faculty from different departments. The primary mission of the project is to make a significant impact on Alzheimer's disease. An equally important objective is to prepare students for future interdisciplinary research by gaining knowledge in a multiple research areas, learning and refining laboratory skills, and interpreting, presenting, and publishing meaningful results. PUBLIC HEALTH RELEVANCE: Deaths from Alzheimer's disease (AD) have increased by 45% from 2000 to 2005, while deaths from heart disease, breast cancer, prostate cancer, and stroke have declined during the same time period. AD is projected to reach epic proportions by the middle of the 21st century overwhelming medical resources. The most appropriate way to develop treatments that will prevent or treat AD is to understand the underlying biochemical features of the disease. This proposal will examine molecular mechanisms linking AD and the human immune response potentially leading to therapies that utilize our own immune system to fight AD. Furthermore, the project will incorporate rigorous research training of students at all levels that will ultimately have a positive long-term impact on public health.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是痴呆症增加并最终死亡。 AD的杰出病理特征包括严重的神经元丧失，老年斑块和弥漫性沉积物中聚集的淀粉样蛋白蛋白（A a）的积累以及神经原纤维tau Tangles。人们普遍认为，积累是广告的主要原因，但仍有几个中心问题。 1）什么结构，聚集状态或物种有助于AD？ 2）人类免疫系统如何识别和对A？？重要的数据表明，广告大脑中对A的持续炎症反应，包括在A沉积物周围的活化小胶质细胞和细胞因子聚类。令人惊讶的是，并非所有的沉积物都会引起炎症反应，这表明A形态/结构会影响反应。这些结果引发了一些关于A引起炎症反应的机制的难题问题。最近的工作已经确定，先天免疫系统的Toll样受体（TLR）介导了促炎反应对汇总的促进反应，这表明A可能具有类似于微生物大分子的结构元素。该提案中的工作将利用生物物理和细胞研究来建立A形态/结构与原代小胶质细胞和星形胶质细胞中感染之间的联系。第一个研究目的将研究影响A聚集和结构的各种条件，并确定导致原代小胶质细胞和星形胶质细胞中最大促炎活性（细胞因子产生）的条件。多种生物物理技术将用于进一步了解A结构与神经胶质激活之间的联系。第二个研究目的将利用正常和转基因基因敲除小鼠来识别和表征TLR，共受体和蛋白质辅因子的复合物，这些辅助因子在神经胶质细胞表面和细胞内部介导生物活性。进一步理解A ??活动可能有助于解释为什么人类免疫系统在控制AD方面无效并提供合法的理论点。该项目的科学和生物医学重要性是它对对阿尔茨海默氏病的理解的直接贡献。该项目的附加和同样重要的方面是它为研究生和本科研究人员提供的培训机会。拟议的研究是细胞生物学，生物化学，生物物理学，纳米科学和光谱的融合，将吸引一群多样的学生参加跨学科研究。广泛的科学将促进来自不同部门的学生和教师之间的合作工作以及互动。该项目的主要任务是对阿尔茨海默氏病产生重大影响。一个同样重要的目标是通过在多个研究领域获得知识，学习和完善实验室技能，解释，呈现和发布有意义的结果，使学生为未来的跨学科研究做好准备。 公共卫生相关性：从2000年到2005年，阿尔茨海默氏病（AD）的死亡人数增加了45％，而心脏病，乳腺癌，前列腺癌和中风的死亡人数在同一时期下降。预计在21世纪中叶，AD将达到史诗般的比例。开发预防或治疗AD的治疗方法的最合适方法是了解该疾病的基本生化特征。该提案将检查将AD和人类免疫反应联系起来的分子机制，可能导致疗法利用我们自己的免疫系统来对抗AD。此外，该项目将在各个级别的学生中进行严格的研究培训，最终将对公共卫生产生积极的长期影响。

项目成果

Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40 mixtures.

• DOI: 10.1016/j.abb.2016.03.017
• 发表时间: 2016-05-01
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Terrill-Usery SE;Colvin BA;Davenport RE;Nichols MR
• 通讯作者: Nichols MR

Amyloid-β42 protofibrils are internalized by microglia more extensively than monomers.

• DOI: 10.1016/j.brainres.2016.08.016
• 发表时间: 2016-10-01
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Gouwens LK;Makoni NJ;Rogers VA;Nichols MR
• 通讯作者: Nichols MR

Amyloid-β(1-42) protofibrils formed in modified artificial cerebrospinal fluid bind and activate microglia.

• DOI: 10.1007/s11481-012-9424-6
• 发表时间: 2013-03
• 期刊: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
• 影响因子: 6.2
• 作者: Paranjape, Geeta S.;Terrill, Shana E.;Gouwens, Lisa K.;Ruck, Benjamin M.;Nichols, Michael R.
• 通讯作者: Nichols, Michael R.

Disentangling aggregation-prone proteins: a new method for isolating α-synuclein species: An Editorial Highlight for "A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oli

解开易于聚集的蛋白质：一种分离 α-突触核蛋白种类的新方法：“一种简单、通用且强大的基于离心的过滤方案，用于分离和定量 α-突触核蛋白单体、oli

• DOI: 10.1111/jnc.14973
• 发表时间: 2020
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Nichols,MichaelR

Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia.

尽管小胶质细胞中细胞内 IL-1β 积累显着，但淀粉样蛋白-β(1-42) 原纤维仍会刺激大量分泌的 IL-1β。

• DOI: 10.1016/j.bbadis.2014.08.001
• 发表时间: 2014-11
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Terrill-Usery, Shana E.;Mohan, Michael J.;Nichols, Michael R.
• 通讯作者: Nichols, Michael R.