Targeting CNS neuroinflammation in animal models of Alzheimer's disease

靶向阿尔茨海默病动物模型中的中枢神经系统神经炎症

• 批准号: 9896439
• 负责人: Howard L Weiner
• 金额: $ 47.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896439
• 关键词: 3xTg-AD mouse; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Animal Model; Anti-Inflammatory Agents; Antibodies; Attenuated; Autopsy; Axon; Behavior; Biological; Biological Markers; Brain; Brain Injuries; CD3 Antigens; Cells; Cervical lymph node group; Data; Dementia; Developed Countries; Disease; Disease Progression; Elderly; High-Throughput RNA Sequencing; Homeostasis; Human; Immune; Immune response; Inflammation; Inflammatory; Innate Immune System; Interleukin-10; Investigation; Knockout Mice; Label; Laboratories; Lead; Measures; Mediating; Microglia; Monoclonal Antibodies; Mus; Nature; Nerve Degeneration; Neurons; Nose; Pathogenesis; Pathway interactions; Phagocytes; Phenotype; Play; Positron-Emission Tomography; Property; Published Comment; Radio; Role; Route; Senile Plaques; Short-Term Memory; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tracer; Travel; behavior test; conditional knockout; immune activation; immunoregulation; improved; in vivo; interleukin-10 receptor; mouse model; neuroinflammation; neuropathology; novel; novel strategies; radiotracer; response; restoration; treatment effect; treatment strategy

PROJECT SUMMARY/ABSTRACT This is a revised application. Neuroinflammation has been identified as a major contributing factor to the pathogenesis of Alzheimer’s disease (AD). Studies showing activated microglia surrounding Aβ plaques in the postmortem AD brain suggest significant involvement of inflammatory pathways in disease progression. PET imaging of AD patients with radio labeled tracers for microglial activation has confirmed these findings. Neuroinflammation involvement of microglia has also been observed in animal models used to study AD. However, the investigation of microglia in AD has been hampered by the lack of specific molecules for understanding microglial phenotype and function and equally as important there is the lack of therapeutic approaches that can target microglia and neuroinflammation. We hypothesize that neuroinflammation is an important target for developing new treatments for AD and that by dampening microglial neuroinflammation with our novel approach (nasal anti-CD3) we will be able to treat AD. We found that nasal anti-CD3 induces an anti-inflammatory immune response that attenuates neuroinflammation in brain-resident microglia cells. In new preliminary data, we found that nasal anti-CD3 improved short-term memory in an AD mouse model. We have found that nasally administered anti-CD3 localizes to cervical lymph nodes where it induces IL-10 secreting T cells that then migrate to the brain and suppress neuroinflammation in microglia. Thus, nasal administration of anti-CD3 is a unique and unexplored target for treating neuroinflammation in AD. The objective of this proposal is to obtain investigate the potential of nasal anti-CD3 to dampen microglia neuroinflammation as a treatment strategy in AD. Aim 1. Investigate the effect of nasal anti-CD3 on microglia phenotype and phagocytic function in aging. Nasal anti-CD3 will be given to 24-month old mice to assess the effect of treatment on in vivo microglia phagocytic function and restoration of microglia homeostasis. We will also measure the induction of IL-10- secreting T cells in the periphery of these mice, which will serve as an easily measured biomarker and on the role of IL-10 on mediating the effect of nasal anti-CD3 on microglia function in aging. Furthermore, we will use IL-10Rflox/floxCX3CR1Cre conditional knockout mice, which do not express the IL-10 receptor on microglia to investigate the role of IL-10 in microglia phagocytic properties as well as its ability to degrade Ab plaques. Aim 2. Investigate the effect of nasal anti-CD3 in the 3xTg AD model. We will perform detailed behavior analysis and neuropathology on 3xTg AD mice treated with nasal anti-CD3 to determine the biological effect and therapeutic potential of anti-CD3. Moreover, we will investigate the effect of nasal anti-CD3 treatment on microglial neuroinflammation in this mouse model of AD using high throughput RNA sequencing (Smart-Seq2).

项目摘要/摘要 这是一个修订的应用程序。神经炎症已被确定为促成 阿尔茨海默氏病（AD）的发病机理。研究表明，在Aβ斑块周围活化的小胶质细胞 尸体后大脑表明炎症途径在疾病进展中的显着参与。宠物 用无线电标记的小胶质细胞激活的广播标记示踪剂的AD成像证实了这些发现。 在用于研究AD的动物模型中，还观察到了小胶质细胞的神经炎症受累。 然而，由于缺乏特定分子而对AD中的小胶质细胞的研究受到了阻碍。 了解小胶质表型和功能，同样重要的是缺乏治疗 可以靶向小胶质细胞和神经炎症的方法。我们假设神经炎症是 为AD开发新疗法的重要目标，并通过使小胶质细胞涂抹 通过我们的新方法（鼻抗CD3），神经炎症我们将能够治疗AD。 我们发现鼻抗CD3会诱导抗炎免疫响应，从而减弱 脑居民小胶质细胞中的神经炎症。在新的初步数据中，我们发现鼻抗CD3 在AD鼠标模型中改善了短期内存。我们发现鼻施用抗CD3 本地化到宫颈淋巴结，其中诱导IL-10分泌的T细胞，然后迁移到大脑， 抑制小胶质细胞中的神经炎症。那是抗CD3的鼻腔给药是一种独特而出乎意料的 治疗AD中神经炎症的靶标。该提议的目的是获得研究潜力 鼻抗CD3的小胶质细胞神经炎症作为AD的治疗策略。 AIM 1。研究鼻抗CD3对小胶质细胞表型和吞噬功能的影响 老化。鼻抗CD3将被给予24个月大的小鼠，以评估治疗对体内小胶质细胞的影响 小胶质细胞稳态的吞噬功能和恢复。我们还将测量IL-10-的诱导 在这些小鼠的周围分泌T细胞，这将作为易于测量的生物标志物，并在 IL-10对介导鼻抗CD3对小胶质细胞功能在衰老中的作用的作用。此外，我们将使用 IL-10RFLOX/FLOXCX3CR1CRE条件敲除小鼠，它们在小胶质细胞上不表达IL-10受体 研究IL-10在小胶质细胞吞噬性质中的作用及其降解AB斑块的能力。 AIM 2。研究鼻抗CD3在3XTG AD模型中的效果。我们将执行详细的行为 对用鼻抗CD3处理的3XTG AD小鼠的分析和神经病理学，以确定生物学作用 抗CD3的治疗潜力。此外，我们将研究鼻抗CD3治疗对 使用高吞吐量RNA测序（SMART-SEQ2），在此AD的小鼠模型中的小胶质细胞神经炎症。

项目成果

Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer's disease.

• DOI: 10.1073/pnas.2309221120
• 发表时间: 2023-09-12
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Lopes, Juliana R.;Zhang, Xiaoming;Mayrink, Julia;Tatematsu, Bruna K.;Guo, Lydia;LeServe, Danielle S.;Abou-El-Hassan, Hadi;Rong, Felipe;Dalton, Maria J.;Oliveira, Marilia G.;Lanser, Toby B.;Liu, Lei;Butovsky, Oleg;Rezende, Rafael M.;Weiner, Howard L.
• 通讯作者: Weiner, Howard L.