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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

基本信息

批准号：
10549778
负责人：
Jaime Grutzendler
金额：
$ 62.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10549778
关键词：
Ablation Affect Aging Alzheimer&apos s Disease Amyloid 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 abeta accumulation anti-PD-1 apolipoprotein E-3 apolipoprotein E-4 cell type extracellular genetic manipulation genetic variant high resolution imaging human imaging hyperphosphorylated tau immune checkpoint improved in vivo in vivo optical imaging mouse model neuropathology neuroprotection neutralizing antibody novel overexpression prevent programmed cell death ligand 1 programmed cell death protein 1 receptor reconstruction response restraint superresolution imaging targeted treatment two-photon ultra high resolution

项目摘要

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.

项目概要小胶质细胞和星形胶质细胞长期以来一直被怀疑参与阿尔茨海默病的发病机制（广告）。然而，目前尚不清楚这些细胞如何协调 AD 中的反应以及它们是否发挥保护作用。或可作为治疗目标的有害作用。我们最近发现了一种潜在的神经保护作用我们称之为“小胶质细胞屏障”的功能。我们发现 Aβ 沉积物的牢固封装小胶质细胞过程导致 Aβ 聚集体变得紧凑、毒性较小并与邻近的神经突隔离，从而减少营养不良轴突的形成。小鼠的这种神经保护功能被严重破坏缺乏 Trem2 或 Dap12，它们在小胶质细胞向斑块极化方面存在缺陷，导致更加弥散斑块构象和轴突营养不良的恶化。在本提案中，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体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进行研究星形胶质细胞和小胶质细胞的细胞和分子基础协调相互作用和极化淀粉样蛋白沉积物。我们还将探索可靶向增强这种神经保护作用的信号通路神经胶质屏障并减少 AD 相关的轴突病理。