Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA.
Rockefeller Neuroscience Institute, Morgantown, WV, USA.
J Alzheimers Dis. 2019;68(3):1257-1271. doi: 10.3233/JAD-190043.
Previous studies have shown tumor necrosis factor-alpha (TNF-α) may impact neurodegeneration in Alzheimer's disease (AD) by regulating amyloid-β and tau pathogenesis. However, it is unclear whether TNF-α has a role in a cholesterol-fed rabbit model of AD or TNF-α affects the electrophysiological properties of rabbit hippocampus. This study was designed to investigate whether long-term feeding of cholesterol diet known to induce AD pathology regulates TNF-α expression in the hippocampus and whether TNF-α would modulate electrophysiological properties of rabbit hippocampal CA1 neurons. TNF-α ELISA showed dietary cholesterol increased hippocampal TNF-α expression in a dose-dependent manner. Whole-cell recordings revealed TNF-α altered the membrane properties of rabbit hippocampal CA1 neurons, which was characterized by a decrease in after-hyperpolarization amplitudes; Field potential recordings showed TNF-α inhibited long-term potentiation but did not influence presynaptic function. Interestingly, TNF-α did not significantly affect the after-hyperpolarization amplitudes of hippocampal CA1 neurons from cholesterol fed rabbits compared to normal chow fed rabbits. In conclusion, dietary cholesterol generated an in vivo model of chronic TNF-α elevation and TNF-α may underlie the learning and memory changes previously seen in the rabbit model of AD by acting as a bridge between dietary cholesterol and brain function and directly modulating the electrophysiological properties of hippocampal CA1 neurons.
先前的研究表明，肿瘤坏死因子-α（TNF-α）可能通过调节淀粉样蛋白-β和 tau 的发病机制来影响阿尔茨海默病（AD）中的神经退行性变。然而，TNF-α 是否在 AD 的胆固醇喂养兔模型中起作用，或者 TNF-α 是否影响兔海马的电生理特性，目前尚不清楚。本研究旨在探讨长期给予已知可诱导 AD 病理的胆固醇饮食是否会调节海马中的 TNF-α 表达，以及 TNF-α 是否会调节兔海马 CA1 神经元的电生理特性。TNF-α ELISA 显示，膳食胆固醇以剂量依赖的方式增加海马 TNF-α 的表达。全细胞膜片钳记录显示，TNF-α改变了兔海马 CA1 神经元的膜特性，其特征是后超极化幅度减小；场电位记录显示，TNF-α抑制长时程增强，但不影响突触前功能。有趣的是，与正常饲料喂养的兔子相比，TNF-α对胆固醇喂养的兔子海马 CA1 神经元的后超极化幅度没有显著影响。总之，饮食胆固醇产生了一种体内慢性 TNF-α 升高模型，TNF-α 可能通过作为饮食胆固醇与大脑功能之间的桥梁，并直接调节海马 CA1 神经元的电生理特性，来解释先前在 AD 兔模型中观察到的学习和记忆变化。
