ArhGAP11A mediates amyloid-β generation and neuropathology in an Alzheimer’s disease-like mouse model
Ya-ru Huang,
Xi-xiu Xie,
Jing Yang,
Xiao-ying Sun,
Xiao-yun Niu,
Cheng-gang Yang,
Ling-jie Li,
Lun Zhang,
Dan Wang,
Chun-yu Liu,
Sheng-jie Hou,
Chen-yang Jiang,
Yu-ming Xu,
Rui-tian Liu
Affiliations
Ya-ru Huang
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
Xi-xiu Xie
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
Jing Yang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Medical Key Laboratory of Neurogenetic and Neurodegenerative Disease, Zhengzhou 450052, Henan, China
Xiao-ying Sun
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
Xiao-yun Niu
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; Ningxia University, Yinchuan 750021, Ningxia, China
Cheng-gang Yang
Department of BigData, Beijing Medintell Bioinformatic Technology Co., Ltd., Beijing 100081, China; Department of Research and Development, Gu’an Bojian Bio-Technology Co., Ltd., Langfang 065000, Hebei, China
Ling-jie Li
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
Lun Zhang
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
Dan Wang
Department of BigData, Beijing Medintell Bioinformatic Technology Co., Ltd., Beijing 100081, China
Chun-yu Liu
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; Shandong Agricultural University, Tai’an 271000, Shandong, China
Sheng-jie Hou
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
Chen-yang Jiang
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
Yu-ming Xu
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Key Laboratory of Cerebrovascular Disease of Henan Province, Zhengzhou 450052, Henan, China; Corresponding author
Rui-tian Liu
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; Corresponding author
Summary: Amyloid-β (Aβ) plays an important role in the neuropathology of Alzheimer’s disease (AD), but some factors promoting Aβ generation and Aβ oligomer (Aβo) neurotoxicity remain unclear. We here find that the levels of ArhGAP11A, a Ras homology GTPase-activating protein, significantly increase in patients with AD and amyloid precursor protein (APP)/presenilin-1 (PS1) mice. Reducing the ArhGAP11A level in neurons not only inhibits Aβ generation by decreasing the expression of APP, PS1, and β-secretase (BACE1) through the RhoA/ROCK/Erk signaling pathway but also reduces Aβo neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of the ArhGAP11A level in neurons significantly reduces Aβ production and plaque deposition and ameliorates neuronal damage, neuroinflammation, and cognitive deficits. Moreover, Aβos enhance ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle. Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis and that decreasing ArhGAP11A expression may be a promising therapeutic strategy for AD treatment.
