Mechanisms of axonal protection by astrocytes and microglia inAlzheimer disease

星形胶质细胞和小胶质细胞在阿尔茨海默病中的轴突保护机制

• 批准号: 10319743
• 负责人: Jaime Grutzendler
• 金额: $ 62.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319743
• 关键词: Ablation; Affect; Aging; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloidosis; Apolipoprotein E; Apoptosis; Astrocytes; Autopsy; Axon; Brain; CRISPR/Cas technology; CTLA4 gene; Cells; Cues; Data; Defect; Deposition; Disease; Encapsulated; Exposure to; Goals; Human; Image; Impairment; Individual; Inflammatory; Knock-out; Ligands; Mediating; Membrane; Methods; Microglia; Microscopy; Molecular; Molecular Conformation; Mus; Neurites; Neuroglia; Neuronal Dysfunction; Neurons; Optics; Pathogenesis; Pathology; Pattern; Pharmacological Treatment; Play; Process; Property; Proteins; Reaction; Resolution; Role; Senile Plaques; Signal Pathway; Signal Transduction; Structure; Surface; Swelling; TREM2 gene; Therapeutic; Time; Variant; Viral; Viral Vector; anti-PD-1; apolipoprotein E-3; apolipoprotein E-4; cell type; extracellular; genetic manipulation; genetic variant; high resolution imaging; human imaging; immune checkpoint; improved; in vivo; mouse model; neuropathology; neutralizing antibody; novel; optical imaging; overexpression; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; reconstruction; response; targeted treatment; tau Proteins; two-photon

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.

项目摘要 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，尚不清楚这些细胞如何协调它们在AD中的反应以及它们是否起保护作用。 或有害的作用，可以作为治疗的目标。我们最近发现了一种潜在的神经保护剂 我们称之为“小胶质细胞屏障”。我们发现，Aβ沉积物的强大封装， 小胶质细胞过程导致Aβ聚集体变得致密，毒性降低，并与相邻的神经突绝缘， 从而减少营养不良轴突的形成。这种神经保护功能在小鼠中被严重破坏 缺乏Trem 2或Dap 12，它们在小胶质细胞向斑块极化方面存在缺陷，导致更加弥漫 斑块形成和轴突营养不良恶化。在本建议中，我们旨在探讨以下可能性： 除了小胶质细胞外，星形胶质细胞对早期淀粉样蛋白聚集的反应以及 这两种细胞类型对于整个神经胶质保护功能至关重要。我们将利用先进的超分辨率 小鼠和人脑成像、活体光学成像和体内单细胞操作，以研究 星形胶质细胞和小胶质细胞的细胞和分子基础协调的相互作用和极化， 淀粉样沉积物我们还将探索可以靶向增强这种神经保护作用的信号通路。 神经胶质屏障和减少AD相关的轴突病理。