Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models

Xiaoqin Zhang; Yufei Mei; Yang He; Dongpi Wang; Jing Wang; Xiaojie Wei; Enlu Yang; Dongming Zhou; Haowei Shen; Guoping Peng; Qiang Shu; Xuekun Li; Benyan Luo; Yudong Zhou; Binggui Sun

doi:10.1016/j.stemcr.2020.12.003

Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models

Stem Cell Reports. 2021 Jan 12;16(1):89-105. doi: 10.1016/j.stemcr.2020.12.003. Epub 2020 Dec 30.

Authors

Xiaoqin Zhang¹, Yufei Mei², Yang He², Dongpi Wang³, Jing Wang², Xiaojie Wei², Enlu Yang², Dongming Zhou³, Haowei Shen⁴, Guoping Peng⁵, Qiang Shu³, Xuekun Li⁶, Benyan Luo⁵, Yudong Zhou⁷, Binggui Sun⁸

Affiliations

¹ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China; Department of Physiology and Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang Province, 315211, China.
² Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
³ Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310052, China.
⁴ Department of Physiology and Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang Province, 315211, China.
⁵ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China.
⁶ Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310052, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310029, China.
⁷ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China. Electronic address: yudongzhou@zju.edu.cn.
⁸ Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China. Electronic address: bsun@zju.edu.cn.

Abstract

Adult neurogenesis is impaired in the hippocampus of patients with Alzheimer disease (AD) as well as AD models. However, it is far from clear how modulating adult neurogenesis affects AD neuropathology. We confirm that adult hippocampal neurogenesis is impaired in two AD models. Surprisingly, however, cognitive functions are improved in AD models after ablating adult neural stem cells (aNSCs). Ablation of aNSCs does not affect the levels of amyloid β but restores the normal synaptic transmission in the dentate gyrus (DG) granule cells of AD models. Furthermore, calbindin depletion in the DG of AD mice is ameliorated after aNSC ablation, and knocking down calbindin abolishes the effects of aNSC ablation on synaptic and cognitive functions of AD mice. Together, our data suggest that cognitive functions of AD mice are improved after aNSC ablation, which is associated with the restoration of synaptic transmission in the DG granule cells with calbindin as an important mediator.

Keywords: Alzheimer's disease; adult neural stem cells; calbindin; cognitive functions; mouse; synaptic transmission.

Publication types

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

MeSH terms

Alzheimer Disease / metabolism
Alzheimer Disease / pathology*
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Calbindins / deficiency
Calbindins / genetics
Cognition / physiology*
Dentate Gyrus / cytology
Dentate Gyrus / metabolism
Disease Models, Animal
Ganciclovir / pharmacology
Humans
Maze Learning
Mice, Transgenic
Neural Stem Cells / cytology
Neural Stem Cells / drug effects
Neural Stem Cells / metabolism*
Presenilin-1 / genetics
Presenilin-1 / metabolism
Synaptic Transmission / physiology*

Substances

Amyloid beta-Protein Precursor
Calbindins
Presenilin-1
Ganciclovir