Dulka Brooke N, Trask Sydney, Helmstetter Fred J
Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States.
Front Aging Neurosci. 2021 Apr 9;13:656944. doi: 10.3389/fnagi.2021.656944. eCollection 2021.
Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females.
衰老的特征是受损和修饰的脑蛋白积累，而泛素-蛋白酶体系统（UPS）对细胞蛋白降解很重要。最近的研究表明UPS在记忆和突触可塑性中起关键作用，但UPS在与年龄相关的认知衰退中的作用仍知之甚少。我们使用痕迹恐惧条件反射（TFC）训练年轻、中年和老年雄性及雌性大鼠，以研究年龄和性别对记忆的影响。然后，我们使用蛋白质印迹法测量与UPS相关的蛋白质降解标记物（Rpt6蛋白酶体调节亚基的磷酸化和K48连接的多泛素化）。我们发现，老年雄性大鼠在记忆提取时表现出行为缺陷，而老年雌性大鼠则没有。老年雄性大鼠在基底外侧杏仁核中还表现出Rpt6蛋白酶体亚基磷酸化减少和K48积累，而老年雌性大鼠在内侧前额叶皮质中表现出类似模式。这些发现表明，UPS功能标记物在不同脑区受到年龄和性别的差异影响。这些结果共同为理解衰老雄性和雌性大鼠的UPS及回路水平差异迈出了重要一步。
