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).

项目总结/摘要 这是一份修改后的申请。神经炎症已被确定为一个主要的促成因素， 阿尔茨海默病（AD）的发病机制。研究显示，活化的小胶质细胞周围的Aβ斑块中， 死后AD脑提示炎症途径在疾病进展中的重要参与。宠物 用放射性标记的示踪剂对AD患者进行的小胶质细胞活化成像证实了这些发现。 在用于研究AD的动物模型中也观察到小胶质细胞的神经炎症参与。 然而，AD中小胶质细胞的研究由于缺乏特异性分子而受到阻碍。 了解小胶质细胞的表型和功能，同样重要的是缺乏治疗方法， 可以针对小胶质细胞和神经炎症的方法。我们假设神经炎症是一种 开发AD新疗法的重要靶点，以及通过抑制小胶质细胞 用我们的新方法（鼻抗CD 3）治疗神经炎症，我们将能够治疗AD。 我们发现，鼻用抗CD 3抗体可诱导抗炎免疫反应， 脑内小胶质细胞的神经炎症。在新的初步数据中，我们发现鼻抗CD 3 改善AD小鼠模型的短期记忆。我们已经发现，鼻腔给药的抗CD 3 定位于颈部淋巴结，在那里它诱导分泌IL-10的T细胞，然后迁移到大脑， 抑制小胶质细胞神经炎症。因此，鼻内给予抗CD 3抗体是一种独特且未经探索的方法。 靶向治疗AD中神经炎症。该提案的目的是获得调查的潜力 鼻腔抗CD 3抑制小胶质细胞神经炎症作为AD的治疗策略。 目标1.研究鼻用抗CD 3抗体对小胶质细胞表型和吞噬功能的影响。 衰老将对24月龄小鼠给予鼻抗CD 3以评估治疗对体内小胶质细胞的影响 吞噬功能和恢复小胶质细胞稳态。我们还将测量IL-10的诱导， 在这些小鼠的外周分泌T细胞，这将作为一个容易测量的生物标志物， IL-10介导鼻抗CD 3对衰老中小胶质细胞功能的作用。此外，我们将使用 IL-10 Rflox/CRCX 3CR 1Cre条件性敲除小鼠，其在小胶质细胞上不表达IL-10受体， 研究IL-10在小胶质细胞吞噬特性中的作用以及其降解Ab噬斑的能力。 目标2.研究鼻用抗CD 3抗体在3xTg AD模型中的作用。我们将执行详细的行为 对用鼻抗-CD 3处理的3xTg AD小鼠进行分析和神经病理学检查以确定生物学效应 和抗CD 3的治疗潜力。此外，我们将研究鼻抗CD 3治疗对 使用高通量RNA测序（Smart-Seq 2）在该AD小鼠模型中检测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.