Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease

项目总结 长期以来，小胶质细胞和星形胶质细胞一直被怀疑参与阿尔茨海默病的发病机制 (Ad)。然而，目前尚不清楚这些细胞如何在AD中协调它们的反应，以及它们是否起到保护作用 或有害的角色，可以作为治疗的靶点。我们最近发现了一种潜在的神经保护 我们称之为“小胶质细胞屏障”的功能。我们发现，Aβ的健壮封装通过 小胶质细胞过程使Aβ聚集体变得致密，毒性较低，并与邻近的神经突起隔绝。 从而减少营养不良轴突的形成。这种神经保护功能在小鼠身上受到了严重破坏 缺乏TREM2或Dap12，这两种基因在小胶质细胞对斑块的极化方面存在缺陷，导致更弥漫 轴索营养不良的斑块形态和恶化。在这项提案中，我们的目标是探索 除小胶质细胞外，星形胶质细胞对早期淀粉样聚集体的反应以及星形细胞与淀粉样蛋白之间的协调反应 这两种细胞类型对整体的神经胶质细胞保护功能至关重要。我们将利用先进的超分辨率 研究小鼠和人脑的成像、活体光学成像和体内单细胞操作 星形胶质细胞和小胶质细胞相互作用和极化的细胞和分子基础 淀粉样物沉积。我们还将探索有针对性的信号通路，以增强这种神经保护 胶质细胞屏障，减轻AD相关轴突病理改变。

PROJECT SUMMARY Microglia and astrocytes have long been suspected of participating in the pathogenesis of Alzheimer’s disease (AD). However, it is not clear how these cells orchestrate their reactions in AD and whether they play protective or deleterious roles that can be targeted therapeutically. We recently discovered a potentially neuroprotective function that we termed the “microglia barrier”. We found that the robust encapsulation of Aβ deposits by microglia processes cause Aβ aggregates to become compact, less toxic and insulated from adjacent neurites, thereby reducing the formation of dystrophic axons. This neuroprotective function was severely disrupted in mice lacking Trem2 or Dap12, which have defects in microglia polarization towards plaques, leading to a more diffuse plaque conformation and worsening of axonal dystrophy. In this proposal, we aim to explore the possibility that in addition to microglia, the astrocytic reaction to early amyloid aggregates and the coordinated reaction between these two cell types is critical for the overall glial protective function. We will utilize sophisticated super-resolution imaging of mouse and human brain, intravital optical imaging and in vivo single cell manipulations to investigate the cellular and molecular basis of astrocyte and microglia orchestrated interactions and polarization towards amyloid deposits. We will also explore signaling pathways that can be targeted to enhance this neuroprotective glial barrier and reduce AD-associated axonal pathology.