中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 2904-2912.doi: 10.4103/NRR.NRR-D-24-00882

• 原著:退行性病与再生 • 上一篇    

神经元中表达的谷氨酸转运体1 介导可溶性Aβ寡聚体可诱导海马长时程增强损害

  

  • 出版日期:2026-07-15 发布日期:2025-10-21

Impairment of hippocampal long-term potentiation by soluble amyloid-β oligomers is mediated by glutamate transporter 1 expressed in neurons

Shaomin Li1, *, †, Jianlin Wang2 , Qianqin Guo1 , Yunxin Bai1 , Wen Liu1 , Kevin J. Hodgetts3 , Paul A. Rosenberg2 , Dennis J. Selkoe1   

  1. 1 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA;  2 Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA;  3 Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women’s Hospital and Harvard Medical School, Cambridge, MA, USA  †Current address: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  • Online:2026-07-15 Published:2025-10-21
  • Contact: Shaomin Li, MD, PhD, sli11@bwh.harvard.edu.
  • Supported by:
    This study was supported by NIH grants P01AG015379 (to DJS), R01 EY027881 (to PAR), R03AG070766 (to PAR), R03AG070766-03 (to SL) and the Davis Amyloid Prevention Program (to DJS).

摘要：

阿尔茨海默病谷氨酸神经递质紊乱会导致突触功能障碍和突触丢失。多项研究利用谷氨酸转运抑制剂证明，可溶性淀粉样β蛋白寡聚体通过干扰谷氨酸转运体1介导的谷氨酸摄取，诱发突触功能障碍。可溶性淀粉样β蛋白寡聚体的突触效应的细胞靶点，包括与谷氨酸转运体1相互作用的性质，仍未明确。实验研究了谷氨酸转运体1敲除小鼠谷氨酸转运体1在细胞类型中的特异功能，并在小鼠海马切片的CA1区检测了场兴奋突触后电位。结果显示，可溶性淀粉样β蛋白寡聚体和谷氨酸摄取抑制剂会诱发海马长时程增强损伤。淀粉样β蛋白寡聚体神经元谷氨酸转运体1基因敲除小鼠中不能抑制海马长时程增强，而在星形胶质细胞谷氨酸转运体1基因敲除小鼠中却不能抑制海马长时程增强。神经元中的谷氨酸转运体1基因敲除掩盖或阻断了可溶性淀粉样β蛋白寡聚体的作用，这表明神经元中的谷氨酸转运体1基因敲除和可溶性淀粉样β蛋白寡聚体抑制突触可塑性的代谢或信号后果显示出了外显性，因此共享相似的分子途径。为了扩展这些观察结果，进一步测试了其他类型的谷氨酸平衡操纵对突触可塑性和可溶性淀粉样β蛋白寡聚体病理生理学的影响。头孢曲松可上调谷氨酸转运体1的水平，还可防止可溶性淀粉样β蛋白寡聚体对长时程增强的损害。总之，实验结果表明，淀粉样β蛋白对突触功能的影响高度依赖于谷氨酸再摄取平衡，可溶性Aβ寡聚体对突触功能的破坏是通过与神经元而非星形胶质细胞的谷氨酸转运体1相关的途径介导的。这项研究的发现凸显了以神经元谷氨酸转运体1为靶点对抗淀粉样β蛋白诱导的阿尔茨海默病突触功能障碍的转化潜力。这项研究表明，上调谷氨酸转运体1（如通过头孢曲松）可预防淀粉样β蛋白相关损伤，从而支持开发旨在调节谷氨酸平衡的疗法，以保护突触功能并对抗阿尔茨海默病的认知能力下降。

https://orcid.org/0000-0001-9451-2151 (Shaomin Li)

关键词: 阿尔茨海默病, 可溶性Aβ寡聚体, 谷氨酸转运体1, 头孢曲松, 海马突触可塑性, 长时程增强, 线粒体, 突触前

Abstract: In Alzheimer’s disease, perturbations of glutamate neurotransmission lead to synaptic dysfunction and synapse loss. Several studies have used glutamate transport inhibitors to demonstrate that soluble oligomers of amyloid-β induce synaptic dysfunction by interrupting glutamate uptake mediated by glutamate transporter 1, the major glutamate transporter in the brain. The cellular targets of the synaptic effects of soluble amyloid-β oligomers, including the nature of any interaction with glutamate transporter 1, remain ill-defined. We have generated a conditional glutamate transporter 1 knockout mouse to investigate celltype specific functions of glutamate transporter 1. Field excitatory postsynaptic potentials were examined in the CA1 region of mouse hippocampal slices. We confirmed that hippocampal long-term potentiation impairment is induced by both soluble Aβ oligomers and glutamate uptake inhibitors. Amyloid-β oligomers, including those isolated directly from the cortex of patients with Alzheimer’s disease, failed to inhibit hippocampal long-term potentiation in neuronal glutamate transporter 1 but not astrocytic glutamate transporter 1 knockout mice. The masking or occlusion of the effect of soluble Aβ oligomers by knockout of glutamate transporter 1 in neurons suggests that the metabolic or signaling consequences of knockout of glutamate transporter 1 in neurons and oAβ inhibition of synaptic plasticity show epistasis and thus share a similar molecular pathway. To extend these observations, we tested the effects of other types of manipulation of glutamate homeostasis on synaptic plasticity and the pathophysiology of soluble Aβ oligomers. Ceftriaxone, which upregulates glutamate transporter 1 levels, among other effects, prevented the impairment of long-term potentiation by soluble Aβ oligomers. Collectively, our findings suggest that the effects of amyloid-β on synaptic function are highly dependent on glutamate reuptake homeostasis and that the disruption of synaptic function by soluble Aβ oligomers is mediated by pathways linked to neuronal, not astrocytic, glutamate transporter 1. This study’s findings highlight the translational potential of targeting neuronal glutamate transporter 1 to counteract amyloid-β-induced synaptic dysfunction in Alzheimer’s disease. By showing that glutamate transporter 1 upregulation (e.g., via ceftriaxone) can prevent Aβ-related impairments, this research supports developing therapies aimed at modulating glutamate homeostasis to preserve synaptic function and combat cognitive decline in patients with Alzheimer’s disease.

Key words: Alzheimer’s disease, soluble Aβ oligomers, glutamate transporter 1, ceftriaxone, hippocampal synaptic plasticity, long-term potentiation, mitochondria, presynaptic