PMID- 33040048
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230201
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 12
IP  - 19
DP  - 2020 Oct 10
TI  - Blockage of AEP attenuates TBI-induced tau hyperphosphorylation and cognitive 
      impairments in rats.
PG  - 19421-19439
LID - 10.18632/aging.103841 [doi]
AB  - Traumatic brain injury (TBI) is regarded as a high-risk factor for Alzheimer's 
      disease (AD). Asparaginyl endopeptidase (AEP), a lysosomal cysteine protease 
      involved in AD pathogenesis, is normally activated under acidic conditions and 
      also in TBI. However, both the molecular mechanism underlying AEP 
      activation-mediated TBI-related AD pathologies, and the role of AEP as an AD 
      therapeutic target, still remain unclear. Here, we report that TBI induces 
      hippocampus dependent cognitive deficit and synaptic dysfunction, accompanied 
      with AEP activation, I(2)(PP2A) (inhibitor 2 of PP2A, also called SET) 
      mis-translocation from neuronal nucleus to cytoplasm, an obvious increase in AEP 
      interaction with SET, and tau hyperphosphorylation in hippocampus of rats. 
      Oxygen-glucose deprivation (OGD), mimicking an acidic condition, also leads to 
      AEP activation, SET mis-translocation, PP2A inhibition, tau hyperphosphorylation, 
      and a decrease in synaptic proteins, all of which are abrogated by AEP inhibitor 
      AENK in primary neurons. Interestingly, AENK restores SET back to the nucleus, 
      mitigates tau pathologies, rescuing TBI-induced cognitive deficit in rats. These 
      findings highlight a novel etiopathogenic mechanism of TBI-related AD, which is 
      initiated by AEP activation, accumulating SET in cytoplasm, and favoring tau 
      pathology and cognitive impairments. Lowering AEP activity by AEP inhibitor would 
      be beneficial to AD patients with TBI.
FAU - Liu, Yi
AU  - Liu Y
AD  - Department of Pathophysiology, Weifang Medical University, Weifang 261053, China.
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Guo, Cuiping
AU  - Guo C
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Ding, Yi
AU  - Ding Y
AD  - Department of Pathophysiology, Weifang Medical University, Weifang 261053, China.
FAU - Long, Xiaobing
AU  - Long X
AD  - Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, 
      University of Science and Technology, Wuhan 430030, China.
FAU - Li, Wensheng
AU  - Li W
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Ke, Dan
AU  - Ke D
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Wang, Qun
AU  - Wang Q
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Liu, Rong
AU  - Liu R
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
FAU - Wang, Jian-Zhi
AU  - Wang JZ
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
AD  - Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, 
      JS, China.
FAU - Zhang, Huaqiu
AU  - Zhang H
AD  - Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, 
      University of Science and Technology, Wuhan 430030, China.
FAU - Wang, Xiaochuan
AU  - Wang X
AD  - Department of Pathophysiology, School of Basic Medicine, Key Laboratory of 
      Education Ministry of China for Neurological Disorders, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430030, China.
AD  - Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, 
      JS, China.
LA  - eng
PT  - Journal Article
DEP - 20201010
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
SB  - IM
PMC - PMC7732271
OTO - NOTNLM
OT  - AEP inhibitor/AENK
OT  - asparaginyl endopeptidase (AEP)
OT  - cognitive impairment
OT  - tau pathology
OT  - traumatic brain injury (TBI)
COIS- CONFLICTS OF INTEREST: The authors declare that they have no conflicts of 
      interest.
EDAT- 2020/10/12 06:00
MHDA- 2020/10/12 06:01
PMCR- 2020/10/15
CRDT- 2020/10/11 20:35
PHST- 2020/06/10 00:00 [received]
PHST- 2020/06/29 00:00 [accepted]
PHST- 2020/10/12 06:00 [pubmed]
PHST- 2020/10/12 06:01 [medline]
PHST- 2020/10/11 20:35 [entrez]
PHST- 2020/10/15 00:00 [pmc-release]
AID - 103841 [pii]
AID - 10.18632/aging.103841 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2020 Oct 10;12(19):19421-19439. doi: 10.18632/aging.103841. 
      Epub 2020 Oct 10.