Transplantation of GABAergic Interneuron Progenitor Attenuates Cognitive Deficits of Alzheimer's Disease Model Mice
Transplantation of GABAergic Interneuron Progenitor Attenuates Cognitive Deficits of Alzheimer's Disease Model Mice
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GABA 能中间神经元祖细胞移植可减轻阿尔茨海默病模型小鼠的认知缺陷
DOI：
10.3233/jad-200010
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Ma, Quan-Hong
中科院分区：
文献类型：
--
作者：
Lu, Mei-Hong;Zhao, Xiu-Yun;Ma, Quan-Hong
神经网络活动的兴奋性(E)和抑制性(I)的平衡对正常的大脑功能是必不可少的，对记忆尤其重要。E/I平衡失调会导致各种神经系统疾病。阿尔茨海默病(AD)中神经兴奋性的出现甚至被认为是认知功能减退加速的预测指标之一。在本研究中，我们发现GAD67(+)、小白蛋白(+)、Calretinin(+)和神经肽Y+中间神经元在APP/PS 1小鼠的脑内逐渐丢失。移植后2个月胚胎内侧神经节隆起来源的中间神经元前体细胞(IP)存活、迁移并成功分化为GABA能中间神经元亚型。移植IP可挽救APP/PS1转基因小鼠受损的突触可塑性和认知缺陷，同时抑制神经的超兴奋性，而移植IP不能减少APP/PS1转基因小鼠的淀粉样β蛋白积聚、神经炎症和突触丢失。这些观察表明，IP移植通过抑制神经超兴奋性改善了APP/PS1转基因小鼠的学习和记忆能力。这项研究强调了GABA能功能障碍在AD发病机制中的作用，以及IP移植在AD治疗中的潜力。
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/PS 1 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/PS 1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-beta 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.