Yeung Jason H Y, Palpagama Thulani H, Tate Warren P, Peppercorn Katie, Waldvogel Henry J, Faull Richard L M, Kwakowsky Andrea
Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Front Neurosci. 2020 Jan 17;13:1427. doi: 10.3389/fnins.2019.01427. eCollection 2019.
Alzheimer's disease (AD) is the leading type of dementia worldwide. Despite an increasing burden of disease due to a rapidly aging population, there is still a lack of complete understanding of the precise pathological mechanisms which drive its progression. Glutamate is the main excitatory neurotransmitter in the brain and plays an essential role in the normal function and excitability of neuronal networks. While previous studies have shown alterations in the function of the glutamatergic system in AD, the underlying etiology of beta amyloid (Aβ) induced changes has not been explored. Here we have investigated the acute effects of stereotaxic hippocampal Aβ injection on specific glutamatergic receptors and transporters in the mouse hippocampus, using immunohistochemistry and confocal microscopy 3 days after Aβ injection in aged male C57BL/6 mice, before the onset of neuronal cell death. We show that acute injection of Aβ is sufficient to induce cognitive deficits 3 days post-injection. We also report no significant changes in glutamate receptor subunits GluA1, GluA2, VGluT1, and VGluT2 in response to acute injection of Aβ when compared with the ACSF-vehicle injected mice. However, we observed increased expression in the DG hilus and ventral stratum (str.) granulosum, CA3 str. radiatum and str. oriens, and CA1 str. radiatum of the GluN1 subunit, and increased expression within the CA3 str. radiatum and decreased expression within the DG str. granulosum of the GluN2A subunit in Aβ injected mice compared to NC, and a similar trend observed when compared to ACSF-injected mice. We also observed alterations in expression patterns of glutamatergic receptor subunits and transporters within specific layers of hippocampal subregions in response to a microinjection stimulus. These findings indicate that the pathological alterations in the glutamatergic system observed in AD are likely to be partially a result of both acute and chronic exposure to Aβ and implies a much more complex circuit mechanism associated with glutamatergic dysfunction than simply glutamate-mediated excitotoxic neuronal death.
阿尔茨海默病（AD）是全球范围内最主要的痴呆类型。尽管由于人口快速老龄化导致疾病负担日益加重，但对于驱动其进展的精确病理机制仍缺乏全面了解。谷氨酸是大脑中的主要兴奋性神经递质，在神经网络的正常功能和兴奋性中起着至关重要的作用。虽然先前的研究表明AD中谷氨酸能系统的功能存在改变，但β淀粉样蛋白（Aβ）诱导变化的潜在病因尚未得到探索。在此，我们研究了立体定向海马注射Aβ对老年雄性C57BL/6小鼠海马中特定谷氨酸能受体和转运体的急性影响，在Aβ注射3天后，即在神经元细胞死亡发生之前，使用免疫组织化学和共聚焦显微镜进行观察。我们发现急性注射Aβ足以在注射后3天诱导认知缺陷。我们还报告称，与注射人工脑脊液（ACSF）的小鼠相比，急性注射Aβ后谷氨酸受体亚基GluA1、GluA2、囊泡谷氨酸转运体1（VGluT1）和囊泡谷氨酸转运体2（VGluT2）没有显著变化。然而，我们观察到，与正常对照组（NC）相比，Aβ注射小鼠的齿状回门区和腹侧颗粒层、CA3放射层和原层以及CA1放射层中谷氨酸受体1亚基（GluN1）的表达增加，并且在Aβ注射小鼠的CA3放射层中表达增加，而在齿状回颗粒层中谷氨酸受体2A亚基（GluN2A）的表达减少，与注射ACSF的小鼠相比也观察到类似趋势。我们还观察到，响应微量注射刺激，海马亚区特定层内谷氨酸能受体亚基和转运体的表达模式发生了改变。这些发现表明，在AD中观察到的谷氨酸能系统的病理改变可能部分是急性和慢性暴露于Aβ的结果，这意味着与谷氨酸能功能障碍相关的回路机制比单纯的谷氨酸介导的兴奋性毒性神经元死亡更为复杂。
