TSPO-PET for the Prediction and Monitoring of Immunomodulatory Effects in Alzheimer's Disease Mouse Models in Conjunction with Amyloid- and Tau-Imaging

正电子发射断层扫描(PET)的分子成像有助于在活体内研究阿尔茨海默病(AD)的神经病理特征。除了众所周知的蛋白质沉积，即β-淀粉样斑块和过度磷酸化的tau纤维外，小胶质细胞的激活代表着AD病理生理学中的一个炎症成分。我们团队在开发新型PET示踪剂以可视化转基因AD小鼠模型中的神经病理标记方面做出了重要贡献。目前研究项目的主要目标是按顺序进行的。首先，我们将研究不同转基因β-淀粉样蛋白和tau小鼠模型中小胶质细胞的激活与异常蛋白沉积的关系，以及使用Morris-Water-和Y-迷宫进行补充的行为/认知评估。在完成纵向PET/行为学研究后，我们将通过组织病理学和生化评估来确认病理。在该项目的第二阶段，我们将测试急性和慢性免疫调节疗法对AD小鼠β-淀粉样蛋白和tau负荷进展的疗效，强调神经炎症-PET对免疫调节对认知测试和体外组织病理学结果的影响的预测价值。在最后阶段，我们将测试抗β-淀粉样蛋白疫苗对神经炎性反应的影响，以及对阿尔茨海默病和AD小鼠认知能力损害的进展的影响。鉴于抗β-淀粉样蛋白疫苗已经进入人体试验，我们相信当前项目的翻译相关性。

Molecular imaging with positron emission tomography (PET) facilitates the investigation of neuropathological hallmarks of Alzheimers disease (AD) in vivo. In addition to the well-known protein depositions, i.e. beta-amyloid plaques and hyperphosphorylated tau-fibrils, the activation of microglia represents an inflammatory component of AD pathophysiology. Our group has contributed importantly in a worldwide effort towards developing novel PET tracers for visualizing neuropathological markers in transgenic AD mouse models. The major aims of the current research project follow in a sequence. First, we shall investigate microglial activation in relation with abnormal protein deposition in different transgenic beta-amyloid and tau mouse models, along with complementary behavioral/cognitive assessment using the Morris-Water- and Y-Mazes. After completion of the longitudinal PET/behavioral study, we shall confirm pathology by histopathological and biochemical assessments. In the second stage of this project, we shall test the efficacy of acute and chronic immunomodulatory therapeutics on the progression of beta-amyloid- and tau-load in the AD mice, emphasizing the predictive value of the neuroinflammation-PET on the effects of immunomodulation on the cognitive testing and in vitro histopathological outcomes. In the final stage, we shall test the effect of an anti-beta-amyloid vaccination on the neuroinflammatory response, and on the progression of amyloidopathy and impaired cognitive performance in AD mice. Given that anti-beta-amyloid vaccines have already entered human trials, we are convinced of the translation relevance of the current project.