Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca(2+) currents (L-VGCC), 4-aminopyridine-sensitive K(+) currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid β-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca(2+) channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K(+) or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca(2+), K(+), AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients.

译文

阿尔茨海默病 (AD) 的神经元变性和死亡之前,可能会发生异常的神经元兴奋性和突触可塑性受损。为了阐明AD中异常神经元网络活动潜在的生物物理变化,我们对L型 (硝苯地平敏感) Ca(2) 电流 (l-vgcc),4-氨基吡啶敏感的K () 电流进行了全细胞膜片钳分析,和AMPA (2-氨基-3-(3-羟基-5-甲基-异恶唑-4-基) 丙酸) 和NMDA (N-甲基-D-天冬氨酸) 电流在海马的CA1,CA3和牙齿颗粒神经元中来自年轻,中年,3xTgAD小鼠和年龄匹配的野生型小鼠。3xTgAD小鼠在海马CA1神经元中发展出淀粉样 β 肽的进行性广泛积累和选择性过度磷酸化的tau病理,这与认知缺陷有关。但与明显的神经元变性无关。3xTgAD小鼠CA1神经元的L型Ca(2) 通道电流密度与年龄有关,但野生型小鼠则没有。在老年3xtgad小鼠中,其幅度明显更大。与老年野生型小鼠相比,老年3xtgad小鼠的CA1神经元中NMDA电流也显着升高。与野生型小鼠相比,3xtgad小鼠的CA1神经元中K () 或AMPA电流的幅度没有差异型小鼠在任何年龄。Ca(2 +),与任何年龄的野生型小鼠相比,来自3xtgad小鼠的CA3和齿状神经元中的K(+),AMPA或NMDA电流。我们的结果揭示了CA1神经元中L-VGCC密度的年龄相关增加,但CA3或齿状颗粒神经元中则没有,3xTgAD小鼠。这些发现表明,L-VGCC改变对3xTgAD小鼠中CA1神经元对tau病理的选择性脆弱性及其在AD患者中的变性的潜在贡献。

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