丙氨酸:阿尔茨海默病的神经生物学机制和治疗潜力。

S. Counts, S. Perez, Ulrika Kahl, Tamas Bartfai, Robert Bowser, Darlene C. Deecher, Deborah C. Mash, Jacqueline N. Crawley, E. Mufson
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引用次数: 41

摘要

哺乳动物中枢神经系统中广泛分布着神经肽甘丙氨酸(GAL)。几条线索的证据表明,GAL可能在认知过程中发挥关键作用,如记忆和注意力通过抑制调节胆碱能基底前脑活动。此外,GAL纤维在阿尔茨海默病(AD)中过度支配剩余的胆碱能基底前脑神经元。这表明GAL活性影响晚期AD的胆碱能功能障碍。药理学和体外放射自显影研究表明,在基底前脑中存在高亲和力和低亲和力的GAL受体(GALR)位点。有趣的是,我们最近观察到晚期AD患者基底前脑前部GALR结合位点增加。迄今为止,已经确定了三种G蛋白偶联的galr,它们通过多种体外效应途径发出信号,包括腺苷酸环化酶抑制和磷脂酶C激活。GALR在基底前脑中的表达范围和分布尚不清楚,AD基底前脑中GALR的性质和GALR的可塑性也不清楚。最近,GAL基因敲除和过表达转基因小鼠的产生有助于我们了解GAL活性在基底前脑功能中的作用。GAL敲除小鼠导致胆碱能基底前脑神经元减少和记忆缺陷。另一方面,过表达GAL的小鼠表现为基底前脑神经支配亢进和记忆缺陷。这些数据强调需要进一步探索GAL信号可能对基底前脑内胆碱能细胞存活和活动有益或有害的假定机制。这一信息对于理解galr的药理学操作是否能有效改善AD患者的认知缺陷至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Galanin: neurobiologic mechanisms and therapeutic potential for Alzheimer's disease.
The neuropeptide galanin (GAL) is widely distributed in the mammalian CNS. Several lines of evidence suggest that GAL may play a critical role in cognitive processes such as memory and attention through an inhibitory modulation of cholinergic basal forebrain activity. Furthermore, GAL fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease (AD). This suggests that GAL activity impacts cholinergic dysfunction in advanced AD. Pharmacological and in vitro autoradiographic studies indicate the presence of heterogeneous populations of GAL receptor (GALR) sites in the basal forebrain which bind GAL with both high and low affinity. Interestingly, we have recently observed that GALR binding sites increase in the anterior basal forebrain in late-stage AD. Three G protein-coupled GALRs have been identified to date that signal through a diverse array of effector pathways in vitro, including adenylyl cyclase inhibition and phospholipase C activation. The repertoire and distribution of GALR expression in the basal forebrain remains unknown, as does the nature of GAL and GALR plasticity in the AD basal forebrain. Recently, GAL knockout and overexpressing transgenic mice have been generated to facilitate our understanding of GAL activity in basal forebrain function. GAL knockout mice result in fewer cholinergic basal forebrain neurons and memory deficits. On the other hand, mice overexpressing GAL display hyperinnervation of basal forebrain and memory deficits. These data highlight the need to explore further the putative mechanisms by which GAL signaling might be beneficial or deleterious for cholinergic cell survival and activity within basal forebrain. This information will be critical to understanding whether pharmacological manipulation of GALRs would be effective for the amelioration of cognitive deficits in AD.
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