Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
J Neurochem. 2020 Oct;155(1):62-80. doi: 10.1111/jnc.15099. Epub 2020 Jul 2.
Alzheimer's disease (AD) is the leading type of dementia worldwide. With an increasing burden of an aging population coupled with the lack of any foreseeable cure, AD warrants the current intense research effort on the toxic effects of an increased concentration of beta-amyloid (Aβ) in the brain. Glutamate is the main excitatory brain neurotransmitter and it plays an essential role in the function and health of neurons and neuronal excitability. While previous studies have shown alterations in expression of glutamatergic signaling components in AD, the underlying mechanisms of these changes are not well understood. This is the first comprehensive anatomical study to characterize the subregion- and cell layer-specific long-term effect of Aβ on the expression of specific glutamate receptors and transporters in the mouse hippocampus, using immunohistochemistry with confocal microscopy. Outcomes are examined 30 days after Aβ stereotactic injection in aged male C57BL/6 mice. We report significant decreases in density of the glutamate receptor subunit GluA1 and the vesicular glutamate transporter (VGluT) 1 in the conus ammonis 1 region of the hippocampus in the Aβ injected mice compared with artificial cerebrospinal fluid injected and naïve controls, notably in the stratum oriens and stratum radiatum. GluA1 subunit density also decreased within the dentate gyrus dorsal stratum moleculare in Aβ injected mice compared with artificial cerebrospinal fluid injected controls. These changes are consistent with findings previously reported in the human AD hippocampus. By contrast, glutamate receptor subunits GluA2, GluN1, GluN2A, and VGluT2 showed no changes in expression. These findings indicate that Aβ induces brain region and layer specific expression changes of the glutamatergic receptors and transporters, suggesting complex and spatial vulnerability of this pathway during development of AD neuropathology. Read the Editorial Highlight for this article on page 7. Cover Image for this issue: https://doi.org/10.1111/jnc.14763.
阿尔茨海默病（AD）是全球范围内主要的痴呆症类型。随着人口老龄化负担的增加，加上缺乏任何可预见的治疗方法，AD 需要当前对大脑中β-淀粉样蛋白（Aβ）浓度增加的毒性作用进行强烈的研究。谷氨酸是大脑中主要的兴奋性神经递质，在神经元的功能和健康以及神经元兴奋性中发挥着重要作用。虽然之前的研究表明 AD 中谷氨酸能信号成分的表达发生了改变，但这些变化的潜在机制尚不清楚。这是第一项使用共聚焦显微镜的免疫组织化学方法，全面描述 Aβ 在雄性 C57BL/6 小鼠海马中的特定谷氨酸受体和转运体表达的亚区和细胞层特异性长期影响的综合解剖学研究。在 Aβ 立体定向注射 30 天后检查结果。与人工脑脊液注射和未处理的对照相比，我们报告说在 Aβ 注射小鼠的海马 CA1 锥体中，谷氨酸受体亚基 GluA1 和囊泡谷氨酸转运体（VGluT）1 的密度显著降低，尤其是在放射层和始层。与人工脑脊液注射对照相比，Aβ 注射小鼠齿状回背侧分子层中的 GluA1 亚基密度也降低。这些变化与先前在人类 AD 海马体中报道的发现一致。相比之下，谷氨酸受体亚基 GluA2、GluN1、GluN2A 和 VGluT2 的表达没有变化。这些发现表明 Aβ 诱导了谷氨酸能受体和转运体的脑区和层特异性表达变化，表明在 AD 神经病理学发展过程中该途径具有复杂和空间易感性。阅读本期文章 7 页的社论重点。本期的封面图片：https://doi.org/10.1111/jnc.14763。
