Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy.
PLoS One. 2012;7(1):e29661. doi: 10.1371/journal.pone.0029661. Epub 2012 Jan 11.
We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA.
METHODOLOGY/FINDINGS: WE USED A DUAL APPROACH: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA.
CONCLUSIONS/SIGNIFICANCE: The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.
我们之前已经表明，β-淀粉样蛋白（Aβ）是一种被认为与阿尔茨海默病相关的肽，它能够作为神经调节剂作用于两种不同的大鼠脑区，在没有明显神经毒性迹象的情况下影响神经递质的释放。在本文中，我们重点关注海马体，这是一个对阿尔茨海默病病理学敏感的脑区，评估 Aβ（在不同浓度下）对被激活的突触前烟碱型乙酰胆碱受体（nAChRs，α4β2 和 α7 亚型）刺激的神经递质释放的影响。特别是，我们专注于一些通常涉及学习和记忆的神经递质：谷氨酸、天冬氨酸和 GABA。
方法/发现：我们使用了一种双重方法：在体实验（自由移动大鼠的微透析技术）与体外实验（源自大鼠海马体的分离神经末梢）平行进行。在体内和体外，尼古丁的给药都刺激了天冬氨酸、谷氨酸和 GABA 的溢出。这种效应被认为是最高浓度的 Aβ（体内 10µM 和体外 100nM）大大抑制。在体内给予 100nM 的 Aβ（考虑的最低浓度）增强了尼古丁引起的 GABA 溢出。所有这些效应都是 Aβ 和烟碱分泌刺激物特异性的。体外给予胆碱或 5-碘-A-85380 二盐酸盐（分别为 α7 和 α4β2 nAChRs 选择性激动剂）都引起了海马体中天冬氨酸、谷氨酸和 GABA 的释放。高浓度的 Aβ（100nM）抑制了由胆碱和 5-碘-A-85380 二盐酸盐引起的所有三种神经递质的溢出。相反，低浓度的 Aβ（1nM 和 100pM）选择性作用于 α7 亚型，增强了胆碱诱导的天冬氨酸和谷氨酸的释放，但不增强 GABA 的释放。
结论/意义：结果强化了 Aβ 具有相关的神经调节作用的概念，这种作用可能从促进到抑制刺激释放，取决于所使用的浓度。
