Ebert Tim, Heinz Daniel E, Almeida-Corrêa Suellen, Cruz Renata, Dethloff Frederik, Stark Tibor, Bajaj Thomas, Maurel Oriana M, Ribeiro Fabiola M, Calcagnini Silvio, Hafner Kathrin, Gassen Nils C, Turck Christoph W, Boulat Benoit, Czisch Michael, Wotjak Carsten T
Research Group Neuronal Plasticity, Max Planck Institute of Psychiatry, Munich, Germany.
Research Group Neurohomeostasis, Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
Front Aging Neurosci. 2021 Nov 12;13:731603. doi: 10.3389/fnagi.2021.731603. eCollection 2021.
Dementia is a devastating age-related disorder. Its therapy would largely benefit from the identification of susceptible subjects at early, prodromal stages of the disease. To search for such prognostic markers of cognitive impairment, we studied spatial navigation in male BALBc vs. B6N mice in combination with magnetic resonance spectroscopy (H-MRS). BALBc mice consistently showed higher escape latencies than B6N mice, both in the Water Cross Maze (WCM) and the Morris water maze (MWM). These performance deficits coincided with higher levels of myo-inositol (mIns) in the dorsal hippocampus before and after training. Subsequent biochemical analyses of hippocampal specimens by capillary immunodetection and liquid chromatography mass spectrometry-based (LC/MS) metabolomics revealed a higher abundance of glial markers (IBA-1, S100B, and GFAP) as well as distinct alterations in metabolites including a decrease in vitamins (pantothenic acid and nicotinamide), neurotransmitters (acetylcholine), their metabolites (glutamine), and acetyl-L-carnitine. Supplementation of low abundant acetyl-L-carnitine via the drinking water, however, failed to revert the behavioral deficits shown by BALBc mice. Based on our data we suggest (i) BALBc mice as an animal model and (ii) hippocampal mIns levels as a prognostic marker of mild cognitive impairment (MCI), due to (iii) local changes in microglia and astrocyte activity, which may (iv) result in decreased concentrations of promnesic molecules.
痴呆是一种与年龄相关的毁灭性疾病。其治疗将极大地受益于在疾病早期、前驱阶段识别易感个体。为了寻找这种认知障碍的预后标志物，我们结合磁共振波谱（H-MRS）研究了雄性BALBc小鼠和B6N小鼠的空间导航能力。在水十字迷宫（WCM）和莫里斯水迷宫（MWM）中，BALBc小鼠的逃避潜伏期始终高于B6N小鼠。这些行为缺陷与训练前后背侧海马中肌醇（mIns）水平升高一致。随后通过毛细管免疫检测和基于液相色谱-质谱联用（LC/MS）的代谢组学对海马标本进行生化分析，结果显示胶质细胞标志物（IBA-1、S100B和GFAP）丰度更高，以及包括维生素（泛酸和烟酰胺）、神经递质（乙酰胆碱）、其代谢产物（谷氨酰胺）和乙酰-L-肉碱在内的代谢物有明显变化。然而，通过饮用水补充低丰度的乙酰-L-肉碱未能逆转BALBc小鼠表现出的行为缺陷。基于我们的数据，我们建议：（i）将BALBc小鼠作为动物模型，（ii）将海马mIns水平作为轻度认知障碍（MCI）的预后标志物，原因是（iii）小胶质细胞和星形胶质细胞活性的局部变化，这可能（iv）导致记忆相关分子浓度降低。
