Role(s) of Microglia in Alzheimer's Disease

小胶质细胞在阿尔茨海默病中的作用(S)仍未解决。的交互作用 含纤维β淀粉样多肽(fAbeta1-42)的小胶质细胞体外刺激 这些细胞分泌过氧化氢和促炎细胞因子。抗炎 药物似乎对阿尔茨海默病的进展和微球有改善作用 分泌产物已被证明对神经元有毒性。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，蛋白多糖在体外阻止小胶质细胞与fAβ的相互作用， 并在体内包被fAbeta，从而抑制小胶质细胞分泌前- 炎性和神经毒性物质，并提示小胶质细胞-α-β 相互作用相对无害。最后，转基因小鼠的治疗 用抗FAP抗体表达人淀粉样前体蛋白(TG-HAPP+/-) 使小胶质细胞能够清除含有fAβ的老年斑样结构 大脑，表明小胶质细胞具有预防和/或阻断的能力 阿尔茨海默病的病理进展。在初步实验中，我们已经证明 介导与fAβ相互作用的表面受体的小胶质细胞表达 受发育调节，成人小胶质细胞上的清道夫受体AI/II，以及 BI在星形胶质细胞上结合FAP，CD36在小胶质细胞分泌过氧化氢时发出信号 附着于含有fAbeta基质，且CD18缺失的小胶质细胞不能 当被镀到这些基质上时，会分泌出过氧化氢。利用从这些项目中获得的见解 FcGamma受体I/II/III-/-和CD18缺失小鼠表达TG的实验 HAPP+/-，我们将探讨小胶质细胞在AD中的作用。建议进行的研究有 五个具体目标：#1.表征表型和基因表达的差异 不同生长因子处理的新生和成年小鼠小胶质细胞的模式， 细胞因子和含有fAβ的基质。#2.确定p2-整合素的作用 在小鼠小胶质细胞和人巨噬细胞对fAβ-的分泌和迁移中 含有杂音的。#3.确定)小鼠小胶质细胞FcGamma和 补体受体在fAβ体外摄取和降解中的作用。#4.评估 含fAβ的基质和野生型CD18分泌产物的作用 Null和FcGamma受体为Null的神经元上的小胶质细胞。#5.确定 CD18 Null-/Tg Happ+/-和FcGamma受体Null/Tg的FAbeta免疫 HAPP+/-小鼠AD样病理改变。

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.