Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment.
Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment.
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DOI：
10.3233/jad-210475
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Iñiguez SD
中科院分区：
文献类型：
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作者：
Sierra-Fonseca JA;Rodriguez M;Themann A;Lira O;Flores-Ramirez FJ;Vargas-Medrano J;Gadad BS;Iñiguez SD
氟西汀（FLX）是治疗儿童情绪相关疾病的首选抗抑郁药。累积的临床前证据表明，个体发育性FLX暴露导致成年期情感相关表型失调。情绪相关的神经系统疾病构成了各种神经系统疾病的风险因素，包括阿尔茨海默病（AD），使青少年FLX病史有可能加剧神经退行性疾病的发展。由于AD的特征是过度磷酸化tau蛋白的病理性积累，这可能是由于蛋白质降解途径（如自噬和泛素-蛋白酶体系统（UPS））功能受损所致，因此我们使用小鼠作为模型系统，评估了青少年FLX暴露对这些途径的长期影响。我们从出生后第35天（PD）至PD 49天对C57 BL/6青春期雄性小鼠进行FLX（20 mg/kg/天）给药。末次FLX注射后21天（即，成年期; PD 70），将小鼠安乐死，并使用免疫印迹分析，我们评估了海马和前额皮质内自噬的蛋白质标志物（Beclin-1，LC 3-II，p62）和UPS（K48-pUb），以及AD相关形式的磷酸化tau。青少年FLX预暴露介导的蛋白质标记物表达的长期变化（增加的LC 3-II和减少的p62），这与自噬激活一致，特别是在前额叶皮层中。此外，FLX病史诱导AD相关tau变体在海马和前额叶皮质中持续蓄积。青少年FLX治疗可能对神经元蛋白降解机制产生持久影响，这可能对异常蛋白的清除产生不利影响，可能使个体在以后的生活中易患AD。
Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortex Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.