Pfizer Global Research and Development, Groton, CT, USA.
Neurobiol Aging. 2012 Jul;33(7):1481.e13-23. doi: 10.1016/j.neurobiolaging.2011.12.010. Epub 2012 Jan 9.
Transgenic mice are used to model increased brain amyloid-β (Aβ) and amyloid plaque formation reflecting Alzheimer's disease pathology. In our study hippocampal network oscillations, population spikes, and long-term potentiation (LTP) were recorded in APPswe/PS1dE9 (APP/PS1) and presenilin1 (PS1) transgenic and wild type mice at 2, 4, and 8 months of age under urethane anesthesia. Hippocampal theta oscillations elicited by brainstem stimulation were similar in wild type and PS1 mice at all age groups. In contrast, APP/PS1 mice showed an age-dependent decrease in hippocampal activity, characterized by a significant decline in elicited theta power and frequency at 4 and 8 months. Magnitudes of population spikes and long-term potentiation in the dentate gyrus were similar across groups at both 4 and 8 months. In APP/PS1 mice, soluble and insoluble Aβ, and hippocampal and cortical plaque load increased with age, and the disruption in hippocampal theta oscillation showed a significant correlation with plaque load. Our study shows that, using in vivo electrophysiological methods, early Aβ-related functional deficits can be robustly detected in the brainstem-hippocampus multisynaptic network.
转基因小鼠被用于模拟增加的脑淀粉样蛋白-β（Aβ）和淀粉样斑块形成，反映阿尔茨海默病病理学。在我们的研究中，在尿嘧啶麻醉下，在 APPswe/PS1dE9（APP/PS1）和早老素 1（PS1）转基因和野生型小鼠 2、4 和 8 个月大时记录海马网络振荡、群体峰和长时程增强（LTP）。由脑干刺激引起的海马θ振荡在野生型和 PS1 小鼠在所有年龄组中均相似。相比之下，APP/PS1 小鼠表现出海马活动的年龄依赖性下降，其特征是在 4 个月和 8 个月时诱发的θ功率和频率显著下降。在 4 个月和 8 个月时，齿状回的群体峰和长时程增强的幅度在各组之间相似。在 APP/PS1 小鼠中，可溶性和不可溶性 Aβ以及海马和皮质斑块负荷随年龄增加而增加，并且海马θ振荡的破坏与斑块负荷呈显著相关性。我们的研究表明，使用体内电生理方法，可以在脑干-海马多突触网络中可靠地检测到与 Aβ 相关的早期功能缺陷。
