Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain.
Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain.
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DOI：
10.1016/j.cellsig.2017.11.004
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发表时间：
2018-01
影响因子：
4.8
通讯作者：
Kelly MP
中科院分区：
文献类型：
--
作者：
Kelly MP
与衰老和年龄相关疾病相关的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以开发改进的药物。在这里，我们回顾了文献，以测试环核苷酸信号在合成，执行和/或降解水平的分解可能导致这些缺陷的假设。在人类和动物模型文献中已经报道了许多发现，指出Galphas的脑区域特异性变化（a.k.a. Gαs或Gsα）、腺苷酸环化酶、3 '，5'-腺苷一磷酸（cAMP）水平、蛋白激酶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）、心房利钠肽（ANP）、脑利钠肽（BNP）、可溶性和颗粒性鸟苷酸环化酶、3 '，5'-鸟苷一磷酸（cGMP）、蛋白激酶G（PKG）和磷酸二酯酶（PDE）。其中最可重复的发现是1）升高的循环ANP和BNP水平与独立于心血管效应的认知功能障碍或痴呆相关，2）在具有老化或阿尔茨海默病（AD）的脑中降低的基础和/或NMDA刺激的cGMP水平，3）在具有老化或AD的海马和特定皮质区域中降低的腺苷酸环化酶活性，4）PKA在患有AD的颞叶皮层和海马中的表达/活性降低，5）CREB在患有衰老或AD的海马中的磷酸化降低，6）PDE 4家族在患有衰老的脑中的表达/活性降低，7）在患有亨廷顿氏病（HD）或帕金森氏病的纹状体中PDE 10A的表达减少，和8）选择的PDE抑制剂，特别是HD模型中的PDE 10抑制剂和衰老和AD模型中的PDE 4和PDE 5抑制剂的有益作用。虽然这些发现通常指出环核苷酸信号的减少与衰老和年龄相关疾病有关，但也有例外。特别是，有证据表明cAMP信号传导增加，特别是在老年前额叶皮层，AD脑血管和PD海马。因此，如果环核苷酸信号传导将被有效地靶向以获得治疗效果，则必须以脑区域特异性的方式对其进行操纵。
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 nucleotidegated 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.
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影响因子：
4
作者：
Arendash, Gary W.;Mori, Takashi;Potter, Huntington
通讯作者：
Potter, Huntington
影响因子：
2.9
作者：
Bonkale, WL;Fastbom, J;Cowburn, RF
通讯作者：
Cowburn, RF
影响因子：
2.5
作者：
Abe, T;Tohgi, H;Sato, C
通讯作者：
Sato, C
影响因子：
6.1
作者：
Baltrons, MA;Pifarré, P;García, A
通讯作者：
García, A
DOI：
10.1007/bf02260966
发表时间：
1994-01-01
期刊：
JOURNAL OF NEURAL TRANSMISSION-PARKINSONS DISEASE AND DEMENTIA SECTION
影响因子：
--
作者：
BOCKELMANN, R;WOLF, G;RIEDERER, P
通讯作者：
RIEDERER, P