CERVO Brain Research Centre, Quebec Mental Health Institute, Québec, QC G1E 1T2, Canada.
Graduate Program in Neuroscience, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada.
Brain. 2023 Dec 1;146(12):4903-4915. doi: 10.1093/brain/awad250.
Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.
阿尔茨海默病早期的去抑制作用被认为会导致网络功能障碍和过度兴奋，从而导致认知缺陷。然而，其潜在的分子机制尚不清楚。在这里，我们表明，在携带阿尔茨海默病相关突变的小鼠系中，负责维持 GABA A 介导的抑制稳健性的神经元膜钾氯离子共转运蛋白 KCC2 会在海马体和前额叶皮层中出现症状前丧失。KCC2 的下调与年龄依赖性增加的淀粉样蛋白-β 42（Aβ42）呈负相关。急性给予 Aβ42 会导致膜 KCC2 的下调。KCC2 的缺失会导致氯离子稳态失调。使用 CLP290 进行长期治疗以防止 KCC2 减少，可预防学习和皮质过度兴奋的恶化。此外，在减少转运蛋白后使用短期 CLP290 治疗来恢复 KCC2，可有效逆转空间记忆缺陷和社交功能障碍，将氯离子失调与阿尔茨海默病相关的认知能力下降联系起来。这些结果表明 KCC2 功能低下是治疗阿尔茨海默病相关认知能力下降的可行靶点；它们证实了治疗干预的作用部位和有效性。
