Duffy Aine M, Morales-Corraliza Jose, Bermudez-Hernandez Keria M, Schaner Michael J, Magagna-Poveda Alejandra, Mathews Paul M, Scharfman Helen E
Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, New York, NY, USA; Department of Child & Adolescent Psychiatry, New York University Langone Medical Center, New York, NY, USA.
Center for Dementia Research, The Nathan Kline Institute for Psychiatric Research, New York, NY, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.
Neurobiol Aging. 2015 Jan;36(1):134-48. doi: 10.1016/j.neurobiolaging.2014.07.001. Epub 2014 Jul 11.
The entorhinal cortex (EC) is one of the first brain areas to display neuropathology in Alzheimer's disease. A mouse model which simulates amyloid-β (Aβ) neuropathology, the Tg2576 mouse, was used to address these early changes. Here, we show EC abnormalities occur in 2- to 4-month-old Tg2576 mice, an age before Aβ deposition and where previous studies suggest that there are few behavioral impairments. First we show, using a sandwich enzyme-linked immunosorbent assay, that soluble human Aβ40 and Aβ42 are detectable in the EC of 2-month-old Tg2576 mice before Aβ deposition. We then demonstrate that 2- to 4-month-old Tg2576 mice are impaired at object placement, an EC-dependent cognitive task. Next, we show that defects in neuronal nuclear antigen expression and myelin uptake occur in the superficial layers of the EC in 2- to 4-month-old Tg2576 mice. In slices from Tg2576 mice that contained the EC, there were repetitive field potentials evoked by a single stimulus to the underlying white matter, and a greater response to reduced extracellular magnesium ([Mg(2+)]o), suggesting increased excitability. However, deep layer neurons in Tg2576 mice had longer latencies to antidromic activation than wild type mice. The results show changes in the EC at early ages and suggest that altered excitability occurs before extensive plaque pathology.
内嗅皮质（EC）是阿尔茨海默病中最早出现神经病理学改变的脑区之一。为了研究这些早期变化，我们使用了一种模拟淀粉样β蛋白（Aβ）神经病理学的小鼠模型——Tg2576小鼠。在此，我们发现2至4月龄的Tg2576小鼠出现了EC异常，这个年龄段在Aβ沉积之前，且此前的研究表明此时几乎没有行为障碍。首先，我们使用夹心酶联免疫吸附测定法表明，在2月龄Tg2576小鼠的Aβ沉积之前，其EC中可检测到可溶性人Aβ40和Aβ42。然后我们证明，2至4月龄的Tg2576小鼠在物体放置任务中表现受损，这是一项依赖于EC的认知任务。接下来，我们发现2至4月龄的Tg2576小鼠EC浅层中神经元核抗原表达和髓鞘摄取存在缺陷。在包含EC的Tg2576小鼠脑片中，对下层白质的单次刺激可诱发重复性场电位，并且对细胞外镁离子浓度降低（[Mg(2+)]o）有更大反应，表明兴奋性增加。然而，Tg2576小鼠深层神经元的逆向激活潜伏期比野生型小鼠更长。结果显示EC在早期就发生了变化，提示在广泛的斑块病理形成之前就出现了兴奋性改变。
