Role of Fibrinogen in Alzheimer's Disease

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种多因素致病的疾病。一个促成因素是 血管功能障碍，这可能是原发性AD发病机制的结果，也可能是神经元损失的原因 以及随后的认知障碍AD和血管系统的分子机制 相互交叉和影响尚不清楚。二十年来，我们一直在努力改进 定义了这种分子间的相互作用。 我们已经证明，β淀粉样蛋白（A β），是AD的驱动因子，与纤维蛋白原相互作用， 增加血凝块的形成。这些凝块具有改变的结构并且对溶解具有抗性。这些 不正常的血栓会导致血流量减少和炎症增加，这两种情况都可能 有助于血管对AD的贡献。 我们现在已经发现A β/纤维蛋白原复合物可以具有不依赖于凝血的毒性作用。在 海马切片培养物中，A β/纤维蛋白原复合物的毒性比单独的A β或纤维蛋白原更大。这些 结果确定了一种新的机制，通过这种机制，A β和纤维蛋白原的相互作用可以导致神经元 功能障碍 A β的突变体和较长形式有时比经典的A β 42和A β 40种类毒性更大。我们 表明某些毒性更强的A β突变体与纤维蛋白原的相互作用更强。这些A β 变异体为研究A β/纤维蛋白原复合物在AD中的毒性机制提供了一个切入点。 因此，我们的主要目标是探索A β变异体及其受体的细胞和分子机制。 纤维蛋白原复合物对大脑有负面影响。

PROJECT SUMMARY Alzheimer's disease (AD) is a multifactorial disorder with many pathogenic elements. One contributing factor is vascular dysfunction, which can be both a result of the primary AD pathogenesis and a cause of neuronal loss and subsequent cognitive impairment. The molecular mechanisms by which AD and the vascular system intersect and influence each other are still unclear. We have been working for two decades to try to better define this molecular interaction. We have shown that beta amyloid (Aβ), the peptide that is a driver of AD, interacts with fibrinogen and increases blood clot formation. These clots have an altered structure and are resistant to lysis. These abnormal clots can contribute to reduced blood flow and increased inflammation, both of which could contribute to vascular contributions to AD. We have now found that the Aβ/fibrinogen complexes can have toxic effects independent of clotting. In hippocampal slice cultures, Aβ/fibrinogen complexes are more toxic than either Aβ or fibrinogen alone. These results identify a new mechanism by which the interaction of Aβ and fibrinogen can lead to neuronal dysfunction. Mutant and longer forms of Aβ are sometimes much more toxic that the classical Aβ42 and Aβ40 species. We show that some mutant forms of Aβ that are more toxic interact much more strongly with fibrinogen. These Aβ variants provide an entrée for studying the mechanisms by which Aβ/fibrinogen complexes are toxic in AD. Therefore, our main goal is to explore the cellular and molecular mechanisms by which Aβ variants and their fibrinogen complexes negatively affect the brain.