Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break down in cyclic nucleotide signaling at the level of synthesis, execution, and/or degradation may contribute to these deficits. A number of findings have been reported in both the human and animal model literature that point to brain region-specific changes in Galphas (a.k.a. Gαs or Gsα), adenylyl cyclase, 3′,5′-adenosine monophosphate (cAMP) levels, protein kinase A (PKA), cAMP response element binding protein (CREB), exchange protein activated by cAMP (Epac), hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), soluble and particulate guanylyl cyclase, 3′,5′-guanosine monophosphate (cGMP), protein kinase G (PKG) and phosphodiesterases (PDEs). Among the most reproducible findings are 1) elevated circulating ANP and BNP levels being associated with cognitive dysfunction or dementia independent of cardiovascular effects, 2) reduced basal and/or NMDA-stimulated cGMP levels in brain with aging or Alzheimer's disease (AD), 3) reduced adenylyl cyclase activity in hippocampus and specific cortical regions with aging or AD, 4) reduced expression/activity of PKA in temporal cortex and hippocampus with AD, 5) reduced phosphorylation of CREB in hippocampus with aging or AD, 6) reduced expression/activity of the PDE4 family in brain with aging, 7) reduced expression of PDE10A in the striatum with Huntington's disease (HD) or Parkinson's disease, and 8) beneficial effects of select PDE inhibitors, particularly PDE10 inhibitors in HD models and PDE4 and PDE5 inhibitors in aging and AD models. Although these findings generally point to a reduction in cyclic nucleotide signaling being associated with aging and age-related diseases, there are exceptions. In particular, there is evidence for increased cAMP signaling specifically in aged prefrontal cortex, AD cerebral vessels, and PD hippocampus. Thus, if cyclic nucleotide signaling is going to be targeted effectively for therapeutic gain, it will have to be manipulated in a brain region-specific manner.

与衰老和年龄相关疾病相关的大脑功能缺陷从目前可用的疗法中获益甚微，这表明需要更好地了解潜在的分子机制来开发改进的药物。在这里，我们回顾了文献来检验这样的假设：合成、执行和/或降解水平上的环核苷酸信号传导的破坏可能导致这些缺陷。人类和动物模型文献中已报道了许多发现，这些发现指出了 Galphas（又名 Gαs 或 Gsα）、腺苷酸环化酶、3',5'-单磷酸腺苷 (cAMP) 水平、蛋白激酶的大脑区域特异性变化A (PKA)、cAMP 反应元件结合蛋白 (CREB)、cAMP 激活的交换蛋白 (Epac)、超极化激活的环核苷酸门控离子通道 (HCN)、心房钠尿肽 (ANP)、脑钠尿肽 (BNP)、可溶性和颗粒性鸟苷酸环化酶、3',5'-单磷酸鸟苷 (cGMP)、蛋白激酶 G (PKG) 和磷酸二酯酶 (PDE)。最可重复的发现包括 1) 循环 ANP 和 BNP 水平升高与认知功能障碍或痴呆相关，与心血管影响无关，2) 衰老或阿尔茨海默病 (AD) 导致大脑中基础和/或 NMDA 刺激的 cGMP 水平降低，3 ) 随着衰老或 AD，海马和特定皮质区域中的腺苷酸环化酶活性降低，4) 随着 AD 的颞叶皮层和海马中 PKA 的表达/活性降低，5) 随着衰老或 AD，海马中 CREB ​​的磷酸化降低，6) 表达/降低随着年龄的增长，大脑中 PDE4 家族的活性下降，7) 患有亨廷顿病 (HD) 或帕金森病的纹状体中 PDE10A 的表达降低，8) 特定 PDE 抑制剂的有益作用，特别是 HD 模型中的 PDE10 抑制剂以及 PDE4 和 PDE5 抑制剂在衰老和 AD 模型中。尽管这些发现通常表明环核苷酸信号传导的减少与衰老和与年龄相关的疾病有关，但也有例外。特别是，有证据表明，在衰老的前额皮质、AD 脑血管和 PD 海马中，cAMP 信号传导增强。因此，如果要有效地靶向环核苷酸信号传导以获得治疗效果，则必须以大脑区域特异性的方式对其进行操作。