Brain aging is accompanied by an accumulation of damaged proteins, which results from deterioration of cellular quality control mechanisms and decreased protein degradation. The ubiquitin-proteasome system (UPS) is the primary proteolytic mechanism responsible for targeted degradation. Recent work has established a critical role of the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. Here, we measured markers of UPS function and related them to fear memory in rats. Our results show that age-related memory deficits are associated with reductions in phosphorylation of the Rpt6 proteasome regulatory subunit and corresponding increases in lysine-48 (K48)-linked ubiquitin tagging within the basolateral amygdala. Increases in K48 polyubiquitination were also observed in the medial prefrontal cortex and dorsal hippocampus. These data suggest that protein degradation is a critical component of age-related memory deficits. This extends our understanding of the relationship between the UPS, aging, and memory, which is an important step toward the prevention and treatment of deficits associated with normal cognitive aging and memory-related neurodegenerative diseases.

中文翻译：

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与年龄相关的记忆缺陷与大脑区域蛋白质降解的变化有关，这些区域对微量恐惧调节至关重要

大脑老化伴随着受损蛋白质的积累，这是由于细胞质量控制机制的恶化和蛋白质降解减少造成的。泛素蛋白酶体系统 (UPS) 是负责靶向降解的主要蛋白水解机制。最近的工作已经确定 UPS 在记忆和突触可塑性中的关键作用，但 UPS 在与年龄相关的认知衰退中的作用仍然知之甚少。在这里，我们测量了 UPS 功能的标志物，并将它们与大鼠的恐惧记忆联系起来。我们的研究结果表明，年龄相关的记忆缺陷与 Rpt6 蛋白酶体调节亚基磷酸化的减少和基底外侧杏仁核内赖氨酸 48 (K48) 相关泛素标记的相应增加有关。在内侧前额叶皮层和背海马体中也观察到 K48 多泛素化的增加。这些数据表明蛋白质降解是与年龄相关的记忆缺陷的关键组成部分。这扩展了我们对 UPS、衰老和记忆之间关系的理解，这是预防和治疗与正常认知衰老和记忆相关神经退行性疾病相关的缺陷的重要一步。