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.

项目概要晚发性阿尔茨海默病 (LOAD) 的全基因组关联研究发现，>70% 的基因座是局部的富含小胶质细胞的基因，小胶质细胞是大脑中最重要的风险变异。 LOAD 是载脂蛋白 E ε4 (APOE4)，其纯合性使 AD 风险增加 >15 倍。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上调小胶质细胞通过清除有毒细胞来防止 AD 的发展。碎片和压实的淀粉样斑块、环境和遗传因素会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加剧疾病。小胶质细胞在 AD 发病机制中的作用、针对小胶质细胞的药理学和细胞治疗干预措施可能能够防止选择性脆弱的大脑区域（例如内嗅区）的 AD 进展在 APPNL-G-F AD 小鼠模型中，这两个区域均显示出淀粉样变性、反应性神经胶质增生、前驱期突触丧失，尤其是内嗅皮层表现出电生理损伤因此，这些区域是新药临床前开发的关键目标。集落刺激因子 1 受体的急性药理抑制疗法。脑渗透药物 PLX5622 已被证明可以选择性诱导小胶质细胞的“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），从而挽救异常的海马活动，促进大脑修复，改善衰老、创伤性脑损伤和产妇的认知缺陷用 APOE3 中性替代 AD 风险（促炎或 APOE4）小胶质细胞。或 APOE2 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，我们研究内嗅皮层的电生理、分子和细胞功能障碍。前驱疾病阶段的海马体是由促炎性反应性小胶质细胞特征驱动的（Aim 1) 和 APOE4 基因型小胶质细胞（目标 2）可以在成年后通过药物强制治疗。 AD 小胶质细胞的更替（目标 1）以及用 APOE 33 或 22 小胶质细胞样细胞替代 AD 小胶质细胞（目标 3）。在目标 1 中，我们将展示内嗅小胶质细胞强制更新的分子和功能变化。在空间导航过程中使用神经元样电子探针观察前驱 AD 小鼠的皮层和海马体在目标 2 中，我们将确定人类小胶质细胞的 APOE 基因型对脆弱性的影响。在目标3中，我们将建立细胞嵌合人/小鼠AD模型中的内嗅和海马神经元。通过将成年小鼠的 AD 小胶质细胞替换为 APOE3 或 APOE2 细胞，在成年期进行替代疗法。本研究的目标是证明 AD 和 APOE 亚型小胶质细胞影响的分子机制神经网络并确定小胶质细胞靶向药理学和人类 iPSC 的功效基于此的治疗策略可以保护 AD 患者中选择性脆弱的神经元和记忆回路。