Dysregulation of protein kinase a signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline
Dysregulation of protein kinase a signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline
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DOI：
10.1016/s0896-6273(03)00694-9
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发表时间：
2003-11-13
期刊：
影响因子：
16.2
通讯作者：
Arnsten, AFT
中科院分区：
文献类型：
--
作者：
Ramos, BP;Birnbaum, SG;Arnsten, AFT
基于海马功能的研究，cAMP/蛋白激酶 A (PKA) 通路的激活被认为是改善与年龄相关的认知缺陷的机制。然而，正常衰老也会影响前额皮质认知功能。在这里，我们报告说，增加 PKA 活性的药物会损害而不是改善患有前额皮质缺陷的老年大鼠和猴子的前额皮质功能。相反，PKA 抑制可改善前额皮质认知缺陷。大鼠大脑的蛋白质印迹和免疫组织化学分析进一步表明，随着年龄的增长，前额皮质中的 cAMP/PKA 通路变得不受抑制。这些数据表明，PKA 抑制而不是激活是恢复老年人前额皮质认知能力的适当策略。
Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.