Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.
Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, China.
J Alzheimers Dis. 2020;75(1):245-260. doi: 10.3233/JAD-200010.
Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer's disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+, Parvalbumin+, Calretinin+, and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-β accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy.
神经网络活动的兴奋(E)和抑制(I)平衡对于正常的大脑功能至关重要，对记忆尤其重要。E/I 平衡的紊乱导致各种神经紊乱。阿尔茨海默病(AD)中出现的神经兴奋性过高甚至被认为是认知衰退加速的预测因素之一。在这项研究中，我们发现 APP/PS1 小鼠大脑中的 GAD67+、Parvalbumin+、Calretinin+和 Neuropeptide Y+中间神经元逐渐丢失。移植的胚胎内侧神经节隆起衍生的中间神经元祖细胞(IPs)在移植后 2 个月成功存活、迁移并分化为 GABA 能中间神经元亚型。海马体移植 IPs 挽救了 APP/PS1 转基因小鼠受损的突触可塑性和认知缺陷，同时抑制了神经兴奋性过高，而移植 IPs 未能减轻 APP/PS1 转基因小鼠的淀粉样蛋白-β积累、神经炎症和突触丢失。这些观察结果表明，移植 IPs 通过抑制神经兴奋性过高改善了 APP/PS1 转基因小鼠的学习和记忆。这项研究强调了 GABA 能功能障碍对 AD 发病机制的因果贡献，以及 IP 移植在 AD 治疗中的潜力。
