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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' 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' s disease; progenitor; protective effect; risk variant; self-renewal; single-cell RNA sequencing; transcriptomics; virtual reality; way finding

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 晚发性阿尔茨海默病（LOAD）的全基因组关联研究发现，>70%的位点是局部的， 到富含小胶质细胞的基因，小胶质细胞是大脑的常驻免疫细胞。最重要的风险变量 LOAD的基因型是载脂蛋白E ε4（APOE 4），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，在淀粉样斑块附近的小胶质细胞中显著上调， 神经退化环境。而小胶质细胞通过清除有毒细胞来保护AD的发展 碎片和压实淀粉样斑块，环境和遗传因素可导致小胶质细胞进入 持续的反应状态，其中它们通过过度炎症和神经毒性使疾病升级。给定 小胶质细胞在AD发病机制中的作用，小胶质细胞靶向药物和细胞治疗干预 可能能够在选择性脆弱的大脑区域（如内嗅神经）中防止AD进展， 皮质和海马体。在APPNL-G-F AD小鼠模型中，两个区域均显示淀粉样变性、反应性神经胶质增生， 前驱期突触丢失，尤其是内嗅皮层出现电生理损害 在认知障碍之前。因此，这些区域是用于临床前开发新的免疫调节剂的关键靶标。 前驱AD的治疗剂。急性药理学抑制集落刺激因子1受体与 脑渗透药物PLX 5622已经显示出选择性地诱导小胶质细胞的“更新”（接近完全 去除现有的小胶质细胞和存活的小胶质细胞的自我更新），其挽救了异常的海马 活动，促进大脑修复，并改善衰老，创伤性脑损伤和孕产妇的认知缺陷 免疫激活模型用APOE 3中性替代AD风险（促炎或APOE 4）小胶质细胞 或APOE 2保护性人iPSC衍生的小胶质细胞可能是一种有前途的小胶质细胞靶向AD治疗剂。 因此，我们假设内嗅皮层的电生理、分子和细胞功能障碍 在前驱疾病阶段的海马是由促炎反应性小胶质细胞信号驱动的（Aim 1)APOE 4基因型小胶质细胞（Aim 2）。它可能在成年后被强迫治疗- AD小胶质细胞的转换（Aim 1）和AD小胶质细胞被APOE 33或22小胶质细胞样细胞替代（Aim 3）。 在目标1中，我们将展示内嗅神经元上小胶质细胞强制转换的分子和功能变化， 用神经元样电子探针研究前驱AD小鼠大脑皮层和海马的空间导航行为 虚拟现实在目标2中，我们将确定人类小胶质细胞的APOE基因型对细胞脆弱性的影响。 嵌合人/小鼠AD模型中的内嗅和海马神经元。在目标3中，我们将建立细胞 通过在成年小鼠中将AD小胶质细胞替换为APOE 3或APOE 2细胞，在成年期进行替代治疗。的 本研究的目的是阐明AD和APOE亚型小胶质细胞影响 神经元网络，并确定小胶质细胞靶向的药理学和人iPSC- 基础的治疗策略保护AD患者中选择性脆弱的神经元和记忆回路。