Duval Nathan, Vacano Guido N, Patterson David
Department of Biological Sciences, Knoebel Institute for Healthy Aging, and Eleanor Roosevelt Institute, University of Denver, Denver, CO, United States.
Front Aging Neurosci. 2018 Sep 6;10:263. doi: 10.3389/fnagi.2018.00263. eCollection 2018.
Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer's disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice.
唐氏综合征（DS）由21号染色体三体性引起，是智力残疾最常见的遗传病因。唐氏综合征患者表现出神经化学和神经解剖学变化，这些变化会随着年龄增长而恶化，存在学习和记忆方面的神经发育迟缓，并且易患阿尔茨海默病。Ts65Dn小鼠是特征最明确的唐氏综合征模型，具有许多与唐氏综合征相似的特征，包括发育异常和与年龄相关的神经退行性变。该小鼠携带小鼠16号染色体的部分三体重复，其中包含大约100个与人类21号染色体基因同源的基因。我们推测，三体性和年龄会导致脑代谢物出现差异，而长期使用雷帕霉素（一种雷帕霉素机制靶点（mTOR）抑制剂和免疫抑制剂）进行治疗将纠正这些差异。通过高效液相色谱结合电化学检测，我们确定了三体小鼠中多巴胺能、血清素能和犬尿氨酸途径中代谢物水平的差异，这些差异会随着年龄增长而加剧。这些代谢物包括高香草酸、去甲肾上腺素和犬尿氨酸。此外，我们证明长期使用雷帕霉素治疗可减少老年小鼠中有毒代谢物（如6 - 羟基褪黑素和3 - 羟基犬尿氨酸）的积累。
