Fu Wen, Jhamandas Jack H
Department of Medicine, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Neurophysiol. 2003 Nov;90(5):3130-6. doi: 10.1152/jn.00616.2003. Epub 2003 Jul 30.
Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by profound deficits in memory and cognitive function. Neuropathological hallmarks of the disease include a loss of basal forebrain cholinergic neurons and the deposition of beta-amyloid peptide (Abeta) in neuritic plaques. At a cellular level, considerable attention has focused on a study of Abeta interactions with the neuronal nicotinic acetylcholine receptor (nAChR) subtypes. In this study, using cell-attached and outside-out single channel recordings from acutely dissociated rat basal forebrain neurons, we report that Abeta and nicotine activate nAChRs with two distinct levels of single-channel conductance. Whole cell recordings from these neurons reveal Abeta and nicotine, in a concentration-dependent and reversible manner, evoke brisk depolarizing responses and an inward current. The effects of Abeta on both single channel and whole cell are blocked by the noncompetitive nAChR antagonist mecamylamine and competitive nAChR antagonist dihydro-beta-erythroidine, but not the specific alpha7-selective nAChR antagonist methyllycaconitine, indicating that Abeta activated non-alpha7 nAChRs on basal forebrain neurons. In addition, the non-alpha7 nAChR agonists UB-165, epibatidine, and cytisine, but not the selective alpha7 agonist AR-R17779, induced similar responses as Abeta and nicotine. Thus non-alpha7 nAChRs may also represent a novel target in mediating the effects of Abeta in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为记忆和认知功能严重受损。该疾病的神经病理学特征包括基底前脑胆碱能神经元的丧失以及β-淀粉样肽（Aβ）在神经炎性斑块中的沉积。在细胞水平上，相当多的注意力集中在研究Aβ与神经元烟碱型乙酰胆碱受体（nAChR）亚型的相互作用上。在本研究中，我们使用急性分离的大鼠基底前脑神经元的细胞贴附式和外向式单通道记录，报告Aβ和尼古丁以两种不同的单通道电导水平激活nAChR。这些神经元的全细胞记录显示，Aβ和尼古丁以浓度依赖性和可逆的方式引起快速去极化反应和内向电流。Aβ对单通道和全细胞的作用均被非竞争性nAChR拮抗剂美加明和竞争性nAChR拮抗剂二氢-β-刺桐啶阻断，但不被特异性α7选择性nAChR拮抗剂甲基lycaconitine阻断，这表明Aβ激活了基底前脑神经元上的非α7 nAChR。此外，非α7 nAChR激动剂UB-165、依博加碱和金雀花碱，但不是选择性α7激动剂AR-R17779，诱导出与Aβ和尼古丁相似的反应。因此，非α7 nAChR也可能是介导Aβ在AD中作用的一个新靶点。
