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

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.

• Authors: Mei-Hong Lu, Xiu-Yun Zhao, De-En Xu, Ji-Bo Chen, Wen-Li Ji, Ze-Ping Huang, Ting-Ting Pan, Lu-Lu Xue, Fen Wang, Qi-Fa Li, Yue Zhang, Ting-Hua Wang, Yuchio Yanagawa, Chun-Feng Liu, Ru-Xiang Xu, Yi-Yuan Xia, Shao Li, Quan-Hong Ma
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 75 Issue 1 Pg. 245-260 ( 2020) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 32280096 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Presenilin-1

Topics

• Alzheimer Disease (genetics, physiopathology, surgery)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Cognition (physiology)
• Cognitive Dysfunction (physiopathology, surgery)
• Disease Models, Animal
• GABAergic Neurons (transplantation)
• Interneurons (transplantation)
• Maze Learning (physiology)
• Mice
• Mice, Transgenic
• Neural Stem Cells (transplantation)
• Presenilin-1 (genetics)