Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Department of Neurology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China.
Cell Commun Signal. 2024 Feb 22;22(1):147. doi: 10.1186/s12964-024-01528-7.
Patients with Alzheimer's disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial.
Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated.
APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice.
Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.
阿尔茨海默病（AD）患者常伴有自发性癫痫发作，这使得临床诊断和治疗变得困难。虽然异常γ-氨基丁酸（GABA）能传递在 AD 和癫痫中都有重要作用，但它仅被认为是谷氨酸损伤的代偿性变化。神经调节蛋白 1（NRG1）-ErbB4 信号可以促进 GABA 的释放并抑制癫痫发生，但它对 AD 认知的影响仍存在争议。
本研究使用 APPswe/PS1dE9 小鼠（APP 小鼠）作为 AD 早期的动物模型。戊四氮急性/慢性化学点燃癫痫模型被建立。脑电图和 Racine 评分被用于评估癫痫发作。行为测试被用于评估认知和情绪。电生理学、western blot 和免疫荧光被用于检测突触、GABA 能系统成分和 NRG1-ErbB4 信号的改变。此外，将 NRG1 脑室给药到 APP 小鼠中，并评估其抗癫痫和认知作用。
APP 小鼠易患癫痫，导致海马突触损伤和认知障碍。电生理分析显示海马 GABA 能传递减少。这种异常的 GABA 能传递涉及到 PV Ins 数量减少和 GABA 合成和转运水平降低。我们还发现了受损的 NRG1-ErbB4 信号，这是由 PV Ins 缺失介导的。NRG1 给药可以有效减少四个月大的 APP 小鼠的癫痫发作并改善认知。
我们的结果表明，异常的 GABA 能传递介导了海马过度兴奋，进一步导致兴奋/抑制失衡，并促进了 AD 早期的癫痫发生。适当的 NRG1 给药可以降低癫痫易感性并挽救认知功能。我们的研究为干预 AD 和癫痫的共病提供了一个潜在的方向。
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