Transplantation of GABAergic Interneuron Progenitor Attenuates Cognitive Deficits of Alzheimer’s Disease Model Mice

Article type: Research Article

Authors: Lu, Mei-Hong^{a; b; 1} | Zhao, Xiu-Yun^{a; b; 1} | Xu, De-En^{c; 1} | Chen, Ji-Bo^{a; b} | Ji, Wen-Li^{a; b} | Huang, Ze-Ping^{a; b} | Pan, Ting-Ting^{a; b} | Xue, Lu-Lu^d | Wang, Fen^{a; b} | Li, Qi-Fa^e | Zhang, Yue^e | Wang, Ting-Hua^d | Yanagawa, Yuchio^f | Liu, Chun-Feng^{a; b} | Xu, Ru-Xiang^g | Xia, Yi-Yuan^{a; b} | Li, Shao^{e; *} | Ma, Quan-Hong^{a; b; *}

Affiliations: [a] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China | [b] Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, China | [c] Department of Neurology, the Second People’s Hospital of Wuxi, Wuxi, Jiangsu Province, China | [d] Institute of Neuroscience, Kunming Medical University, Kunming, China | [e] Department of Physiology, National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian, Liaoning, China | [f] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan | [g] Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

Correspondence: [*] Correspondence to: Dr. Shao Li, National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, Dalian Medical University, Dalian 116000, Liaoning, China. E-mail: [email protected] and Dr. Quan-Hong Ma, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases, Institute of Neuroscience, Soochow University, Suzhou 215004, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Alzheimer’s disease, cell transplantation, GABA, hyperexcitability, interneuron, interneuron progenitor

DOI: 10.3233/JAD-200010

Journal: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 245-260, 2020