Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA Department of Pathology and Cell Biology, Columbia University, New York, NY, USA Center for Neurobiology and Behavior, Columbia University, New York, NY, USA.
J Alzheimers Dis. 2014;38(1):49-62. doi: 10.3233/JAD-130740.
Amyloid-β (Aβ) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although Aβ has been extensively studied as the pathological plaque-forming protein species in Alzheimer's disease (AD), little is known about the normal physiological function(s) and signaling pathway(s). We previously discovered that physiologically-relevant, low picomolar amounts of Aβ can enhance synaptic plasticity and hippocampal-dependent cognition in mice. In this study, we demonstrated that astrocytes are cellular candidates for participating in this type of Aβ signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of Aβ peptides can enhance spontaneous intracellular calcium transient signaling. After application of 200 pM Aβ42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on α7 nicotinic acetylcholine receptors (α7-nAChRs), as the enhancement effects were blocked by a pharmacological α7-nAChR inhibitor and in astrocytes from an α7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar Aβ-induced alterations in propagation parameters. Overall, these results indicate that at a physiologically-relevant low picomolar concentration, Aβ peptides can enhance spontaneous astrocyte calcium transient signaling via α7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, Aβ peptides may have a normal physiological function in regulating neuron-glia signaling. Dysfunction of this signaling process may underlie glia-based aspects of AD pathogenesis.
淀粉样蛋白-β（Aβ）肽在生命过程中通过可受突触活动调节的机制在大脑中持续产生。尽管 Aβ 已被广泛研究为阿尔茨海默病（AD）中形成病理性斑块的蛋白种类，但对于其正常生理功能和信号通路知之甚少。我们之前发现，生理相关的低皮摩尔浓度的 Aβ 可以增强小鼠的突触可塑性和海马依赖性认知。在这项研究中，我们证明了星形胶质细胞是参与这种 Aβ 信号的细胞候选物。通过对原代星形胶质细胞培养物进行钙成像，我们观察到皮摩尔浓度的 Aβ 肽可以增强自发细胞内钙瞬变信号。应用 200 pM Aβ42 肽后，自发胞质钙瞬变的频率和幅度平均值显著增加。这些效应依赖于α7 烟碱型乙酰胆碱受体（α7-nAChR），因为药理学α7-nAChR 抑制剂和来自α7 缺陷小鼠品系的星形胶质细胞可以阻断增强效应。我们还检查了诱发的细胞间钙波信号，但没有检测到 Aβ 在皮摩尔浓度下对传播参数的显著改变。总体而言，这些结果表明，在生理相关的低皮摩尔浓度下，Aβ 肽可以通过 α7-nAChR 增强自发的星形胶质细胞钙瞬变信号。由于星形胶质细胞介导的神经胶质传递先前被发现具有神经调节作用，因此 Aβ 肽可能在调节神经元-胶质细胞信号中具有正常的生理功能。该信号过程的功能障碍可能是 AD 发病机制中基于胶质的方面的基础。
