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：
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
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/10319743
关键词：
Ablation Affect Aging Alzheimer&apos 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

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.

项目摘要长期以来一直怀疑小胶质细胞和星形胶质细胞参与阿尔茨海默氏病的发病机理（广告）。但是，尚不清楚这些细胞如何在AD中编排它们的反应以及它们是否发挥保护作用或可以针对理论的有害角色。我们最近发现了一个潜在的神经保护作用我们称为“小胶质细胞屏障”的功能。我们发现，通过小胶质细胞过程会导致Aβ聚集体变得紧凑，毒性较小，并且与相邻神经运动隔热，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严重中断缺少TREM2或DAP12，它们在小胶质细胞偏振方面存在缺陷，导致更加弥漫斑块构象和轴突营养不良的担忧。在此提案中，我们旨在探讨除小胶质细胞外，星形胶质细胞对早期淀粉样蛋白聚集体的反应和在这两种细胞类型对于整体神经胶质保护功能至关重要。我们将利用复杂的超分辨率小鼠和人脑的成像，插入式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精心策划的相互作用以及极化淀粉样蛋白沉积。我们还将探索可以针对增强这种神经保护的信号通路神经胶质屏障并减少与广告相关的轴突病理学。