Role(s) of Microglia in Alzheimer's Disease

小胶质细胞在阿尔茨海默病中的作用

• 批准号: 6649693
• 负责人: SAMUEL CHARLES SILVERSTEIN
• 金额: $ 35.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649693
• 关键词: Alzheimer's disease; amyloid proteins; cell migration; complement; cytokine; gene expression; growth factor; human tissue; inflammation; integrins; laboratory mouse; macrophage; microglia; molecular pathology; pathologic process

The role(s) of microglia in Alzheimer's disease remain unresolved. interactions of microglia with fibrillar beta amyloid peptides (fAbeta1-42) in vitro stimulates these cells to secrete H2O2, and pro-inflammatory cytokines. Anti-inflammatory drugs appear to exert an ameliorating effect on AD progression, and microgloial secretory products have been shown to be toxic to neurons. These observations suggest that microglia promote nerve damage and speed the progress of AD. Conversely, proteoglycans, block interactions of microglia with fAbeta in vitro, and coat fAbeta in vivo, thereby inhibiting microglial secretion of pro- inflammatory and neurotoxic substances, and suggesting that microglial-fAbeta interactions are relatively innocuous. Finally, treatment of transgenic mice expressing human amyloid precursor protein (Tg hAPP+/-) with anti-fAP IgG enables microglia to clear fAbeta-containing senile plaque-like structures from the brain, suggesting that microglia have the capacity to prevent and/or block progression of AD-like pathology. In preliminary experiments we have shown that microglial expression of surface receptors that mediate interactions with fAbeta is developmentally regulated, that scavenger receptors AI/II on adult microglia, and BI on astrocytes, bind fAP, that CD36 signals H2O2 secretion when microglia adhere to fAbeta-containing matrices, and that CD18 null microglia are incapable of secreting H2O2 when plated on these matrices. Using insights gained from these experiments, and Fcgamma receptor I/II/III-/- and CD18 null mice expressing Tg hAPP+/-, we will explore the roles of microglial in AD . The studies proposed have five specific aims: #1. Characterize differences in phenotype and gene expression patterns of newborn and adult mouse microglia treated with various growth factors, cytokines, and fAbeta-containing matrices. #2. Determine the roles) of p2-integrins in secretion and migration of mouse microglia and human macrophages on fAbeta- containing murices. #3. Determine the roles) of mouse microglial Fcgamma and complement receptors in uptake and degradation of fAbeta in vitro. #4. Assess effects of fAbeta-containing matrices, and of products secreted by wild type, CD18 null and Fcgamma receptor null microglia on neurons. #5. Determine the effects of fAbeta immunization of CD18 null -/Tg hAPP+/- and Fcgamma receptor null/Tg hAPP+/- mice on AD-like pathology.

小胶质细胞在阿尔茨海默病中的作用仍然没有得到解决。相互作用 小胶质细胞与纤维状β淀粉样肽（fAbeta 1 -42）在体外刺激 这些细胞分泌H2 O2和促炎细胞因子。抗炎 药物似乎对AD进展有改善作用， 分泌产物已显示对神经元有毒。这些观察结果 提示小胶质细胞促进神经损伤，加速AD的进展。 相反，蛋白聚糖在体外阻断小胶质细胞与fAbeta的相互作用， 并在体内包被fAbeta，从而抑制小胶质细胞分泌前- 炎症和神经毒性物质，并表明小胶质细胞-fAbeta 相互作用相对无害。最后，转基因小鼠的治疗 用抗fAP IgG表达人淀粉样前体蛋白（Tg hAPP+/-） 使小胶质细胞能够清除含有fAbeta的老年斑样结构， 这表明小胶质细胞有能力阻止和/或阻止 AD样病理学进展。在初步实验中，我们已经表明， 介导与fAbeta相互作用的表面受体的小胶质细胞表达是 发育调节，成年小胶质细胞上的清道夫受体AI/II， BI在星形胶质细胞上，结合fAP，当小胶质细胞 粘附于含fAbeta的基质，并且CD 18无效的小胶质细胞不能 分泌过氧化氢的能力。利用从这些中获得的见解， 实验和表达Tg的Fc γ受体I/II/III-/-和CD 18缺失小鼠 hAPP+/-，我们将探索小胶质细胞在AD中的作用。建议的研究包括 五个具体目标：#1。表征表型和基因表达的差异 用各种生长因子处理的新生和成年小鼠小胶质细胞的模式， 细胞因子和含fAbeta的基质。#2.确定β 2-整联蛋白的作用 小鼠小胶质细胞和人巨噬细胞分泌和迁移对fAbeta- 包含murices。#3.确定小鼠小胶质细胞Fc γ和 补体受体在体外摄取和降解fAbeta中的作用。#4.评估 含fAbeta基质和野生型CD 18分泌产物的作用 空和Fc γ受体空小胶质细胞。#5.确定影响 CD 18 null -/Tg hAPP+/-和Fc γ受体null/Tg的fAbeta免疫 hAPP+/-小鼠对AD样病理的影响。