Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Jie Zheng; Hong-Lian Li; Na Tian; Fei Liu; Lu Wang; Yaling Yin; Lupeng Yue; Longyu Ma; You Wan; Jian-Zhi Wang

doi:10.1016/j.stem.2019.12.015

Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Cell Stem Cell. 2020 Mar 5;26(3):331-345.e6. doi: 10.1016/j.stem.2019.12.015. Epub 2020 Jan 23.

Authors

Jie Zheng¹, Hong-Lian Li², Na Tian², Fei Liu³, Lu Wang⁴, Yaling Yin⁴, Lupeng Yue⁵, Longyu Ma⁶, You Wan⁶, Jian-Zhi Wang⁷

Affiliations

¹ Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhengjiie@163.com.
² Department of Histology and Embryology, Key Laboratory of Ministry of Education of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
³ Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁴ Key Laboratory of Brain Research of Henan Province, Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang 453003, China.
⁵ CAS Key Laboratory of Mental Health, Institute of Psychology, Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China.
⁶ Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
⁷ Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China. Electronic address: wangjz@mail.hust.edu.cn.

PMID: 31978364
DOI: 10.1016/j.stem.2019.12.015

Abstract

Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer's disease (AD), but whether and how tau dysregulates AHN in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.

Keywords: GABA; GABAergic interneuron; adult hippocampal neurogenesis; astrogliosis; cognitive impairment; network hyperactivation; tau accumulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alzheimer Disease*
Animals
Disease Models, Animal
GABAergic Neurons
Hippocampus
Humans
Interneurons
Mice
Neural Stem Cells*
Neurogenesis