Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron. 2019 Mar 20;101(6):1099-1108.e6. doi: 10.1016/j.neuron.2019.01.014. Epub 2019 Feb 5.
Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.
脑血管改变是阿尔茨海默病（AD）发病机制的一个关键特征。然而，血管损伤是否导致突触功能障碍，以及它如何与淀粉样蛋白病理学协同引起神经炎症和认知能力下降，仍知之甚少。在这里，我们表明，血液蛋白纤维蛋白原诱导了突触消除，并通过 CD11b-CD18 小胶质细胞的激活促进了认知缺陷的发生。在清除的小鼠和人类 AD 大脑中进行的 3D 分子标记，结合重复的体内双光子成像，显示出与淀粉样斑块无关的、与树突棘丢失相关的纤维蛋白原焦点沉积。通过抑制活性氧（ROS）的产生或 CD11b 的基因消融，可以防止纤维蛋白原诱导的棘突消除。纤维蛋白原结合到 CD11b 的基序的基因消除减少了 5XFAD 小鼠 AD 模型中的神经炎症、突触缺陷和认知能力下降。因此，纤维蛋白原通过 CD11b 诱导的棘突消除和认知能力下降，将脑血管损伤与免疫介导的神经退行性变联系起来，这可能对 AD 及相关疾病具有重要意义。
