QPS Austria GmbH, Grambach, Austria.
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
J Alzheimers Dis. 2021;80(3):1151-1168. doi: 10.3233/JAD-201204.
Preclinical Alzheimer's disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression.
We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model.
Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses.
Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice.
Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.
临床前阿尔茨海默病（AD）研究强烈依赖于表现出该疾病主要症状的转基因小鼠模型。尽管已经开发了几种代表相关病理学的 AD 小鼠模型，但只有少数可用的小鼠模型，如 Tg4-42 小鼠模型，显示出由神经元死亡引起的海马萎缩，这是 AD 的关键特征。因此，Tg4-42 小鼠模型非常适合用于临床前研究。此外，代谢生物标志物具有检测生化变化的潜力，对于深入了解途径、潜在的病理机制和疾病进展至关重要。
我们因此采用综合方法分析 AD 体内模型中复杂生物网络的变化，对 Tg4-42 小鼠进行了深入的表征。
因此，我们将非靶向性基于 NMR 的代谢组学表型分析与行为测试以及免疫组织化学和生化分析相结合。
我们的体内实验表明，杂合 Tg4-42 小鼠随时间推移体重增加减少，并且在 Morris 水迷宫行为测试中学习行为和记忆缺陷严重。此外，我们在两个不同的脑区发现了明显改变的代谢物，以及谷氨酸/4-氨基丁酸-谷氨酰胺轴的代谢变化。基于这些结果，我们分析了下游效应，显示出 Tg4-42 小鼠中 Aβ42 水平升高、神经炎症增加（表现为星形胶质细胞和小胶质细胞增生增加）以及神经元变性和神经元丢失。
我们的研究提供了对 Tg4-42 小鼠模型的全面表征，这可能导致对 AD 病理特征的更深入理解。此外，这项研究揭示了代谢生物标志物的变化，为未来的临床前研究或药物开发奠定了基础。
