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

作者：Shaomin Li, Jianlin Wang, Qin Guo, Yan Bai, Wen Liu, Kevin J. Hodgetts, Paul A. Rosenberg, Dennis J. Selkoe · 发表于：Neural Regeneration Research · 年份：2025 · DOI：10.4103/nrr.nrr-d-24-00882 · 被引用次数：6 · 研究领域：Neuroscience and Neuropharmacology Research、Alzheimer's disease research and treatments、Epilepsy research and treatment

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. T...