Microglia targeted interventions in prodromal Alzheimer's disease stage

小胶质细胞针对阿尔茨海默病前驱阶段的干预

基本信息

批准号：
10740479
负责人：
Julia TCW
金额：
$ 83.03万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740479
关键词：
Acceleration Acute Adult Affect Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Amyloid Amyloidosis Apolipoprotein E Astrocytes Binding Brain Brain region Cell physiology Cells Cognitive deficits Development Disease Disease Progression Electronics Electrophysiology (science)Environment Excision Exhibits Functional disorder Genes Genetic Genotype Gliosis Goals Hippocampus Human Immune Immunoassay Impaired cognition Impairment Infiltration Inflammation Inflammatory Intervention Intravenous Late Onset Alzheimer Disease Lead Macrophage Colony-Stimulating Factor Receptor Memory Microglia Modeling Molecular Mus Neonatal Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Newborn Infant Pathogenesis Pharmaceutical Preparations Protein Isoforms Proteins Recovery Research Role Senile Plaques Synapses Therapeutic Therapeutic Intervention Traumatic Brain Injury Xenograft procedure antagonist apolipoprotein E-3 brain cell brain repair cell type efficacy evaluation entorhinal cortex genome wide association study immune activation in vivo induced pluripotent stem cell interdisciplinary approach mouse model neurotoxicity novel therapeutics pharmacologic preclinical development prodromal Alzheimer&apos s disease progenitor protective effect risk variant self-renewal single-cell RNA sequencing transcriptomics virtual reality way finding

项目摘要

Project Summary Genome-wide association studies for late-onset Alzheimer’s disease (LOAD) found that >70% loci are localized to genes that are enriched in microglia, the resident immune cells of the brain. The most significant risk variant for LOAD is apolipoprotein E ε4 (APOE4) and its homozygosity increasing AD risk >15-fold. APOE is predominantly expressed in astrocytes and significantly upregulated in microglia near amyloid plaques and by neurodegenerative environments. While microglia protect against development of AD by clearing toxic cellular debris and compacting amyloid plaques, environmental and genetic factors can cause microglia to enter persistent reactive states in which they escalate disease via excessive inflammation and neurotoxicity. Given the role of microglia in AD pathogenesis, microglia-targeted pharmacological and cell therapeutic interventions may be able to protect against AD progression in selectively vulnerable brain regions such as the entorhinal cortex and hippocampus. In the APPNL-G-F AD mouse model, both regions show amyloidosis, reactive gliosis, and synaptic loss in prodromal stages, especially the entorhinal cortex shows electrophysiological impairment prior to cognitive impairment. Thus, these regions are critical targets for preclinical development of novel therapeutics for prodromal AD. Acute pharmacological inhibition of colony stimulating factor 1 receptor with the brain-penetrant drug PLX5622 has been shown to selectively induce “turnover” of microglia (near complete removal of existing microglia and self-renewal of survived microglia), which rescues abnormal hippocampal activity, promotes brain repair, and ameliorates cognitive deficits in aging, traumatic brain injury, and maternal immune activation models. Replacement of AD risk (proinflammatory or APOE4) microglia with APOE3 neutral or APOE2 protective human iPSC-derived microglia may be a promising microglia-targeted AD therapeutic. Therefore, we hypothesize that electrophysiological, molecular, and cellular dysfunctions in the entorhinal cortex and hippocampus at prodromal disease stages is driven by proinflammatory reactive microglia signatures (Aim 1) and APOE4 genotype microglia (Aim 2). It can potentially be treated in adulthood by pharmacologically forced- turnover of AD microglia (Aim 1) and AD microglia replacement with APOE 33 or 22 microglia-like cells (Aim 3). In Aim 1, we will demonstrate molecular and functional changes in forced turnover of microglia on the entorhinal cortex and hippocampus of prodromal AD mice using neuron-like electronic probes during spatial navigation virtual reality. In Aim 2, we will determine APOE genotype effects of human microglia on vulnerability of the entorhinal and hippocampal neurons in chimeric human/mouse AD model. In Aim 3, we will establish cell replacement therapeutics in adulthood by replacing AD microglia to APOE3 or APOE2 cells in adult mice. The goal of this research is to demonstrate molecular mechanisms by which AD and APOE isoform microglia affect neuronal network and to determine the efficacy by which microglia-targeted pharmacological and human iPSC- based therapeutic strategies protect neurons and memory circuits that are selectively vulnerable in AD patients.

项目摘要全基因组的关联研究针对阿尔茨海默氏病（负载）发现> 70％局部对于富含小胶质细胞的基因，大脑的居民免疫了。最重要的风险变体对于负载是载脂蛋白Eε4（APOE4）及其纯合性增加AD风险> 15倍。 Apoe是主要在星形胶质细胞中表达，并在淀粉样斑块附近的小胶质细胞中显着更新神经退行性环境。小胶质细胞通过清除有毒细胞来防止AD的发展碎屑和紧凑的淀粉样斑块，环境和遗传因素可能导致小胶质细胞进入持续的反应性状态通过过度炎症和神经毒性升级疾病。给出小胶质细胞在AD发病机理，靶向小胶质细胞的药物和细胞治疗干预措施中的作用可能能够防止有选择性易受伤害的大脑区域（例如内河）的AD进展皮层和海马。在AppNL-G-F AD小鼠模型中，两个区域均显示淀粉样变性，反应性神经病，和前驱阶段的突触损失，尤其是内嗅皮层显示电生理障碍在认知障碍之前。这是这些区域是新颖的临床前发展的关键目标前驱AD的治疗剂。急性药理抑制菌落刺激因子1受体已显示脑培训药物PLX5622有选择地诱导小胶质细胞的“周转”（接近完整）删除现有的小胶质细胞和生存的小胶质细胞的自我更新），挽救了海马异常活动，促进脑修复并改善衰老，创伤性脑损伤和母体的认知缺陷免疫激活模型。用APOE3中性替代AD风险（促炎或APOE4）小胶质细胞或APOE2保护的人IPSC衍生的小胶质细胞可能是一种有希望的小胶质细胞靶向AD疗法。因此，我们假设内嗅皮质中的电生理，分子和细胞功能障碍前驱疾病阶段的海马由促炎的反应性小胶质细胞特征驱动（AIM 1）和APOE4基因型小胶质细胞（AIM 2）。它可能会在成年期间被药物强制治疗用APOE 33或22个小胶质细胞样细胞（AIM 3）替换AD小胶质细胞（AIM 1）和AD小胶质细胞的营业额。在AIM 1中，我们将展示小胶质细胞强迫周转的分子和功能变化在空间导航期间使用神经元的电子问题的前驱AD小鼠的皮质和海马虚拟现实。在AIM 2中，我们将确定人类小胶质细胞对APOE基因型对脆弱性的影响嵌合人/小鼠AD模型中的内嗅和海马神经元。在AIM 3中，我们将建立单元格成年后，成年后的替代疗法替换为成年小鼠的APOE3或APOE2细胞。这这项研究的目标是证明AD和APOE同工型小胶质细胞的分子机制神经元网络并确定小胶质细胞靶向药物和人IPSC的效率基于治疗策略，可以在AD患者中有选择地易受伤害的神经元和记忆回路。