PMID- 28641077
OWN - NLM
STAT- MEDLINE
DCOM- 20170912
LR  - 20170912
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 187
IP  - 8
DP  - 2017 Aug
TI  - Inhibition of Early Growth Response 1 in the Hippocampus Alleviates 
      Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and 
      Tangles.
PG  - 1828-1847
LID - S0002-9440(17)30304-8 [pii]
LID - 10.1016/j.ajpath.2017.04.018 [doi]
AB  - A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk 
      factors, and their pathogenic mechanisms are suggested to be related. 
      Transcription factor early growth response 1 (Egr-1) regulates various vascular 
      pathologies and is up-regulated in both AD brains and AD mouse models; however, 
      its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 
      in the hippocampus by shRNA reduces tau phosphorylation, lowers amyloid-beta (Abeta) 
      pathology, and improves cognition in the 3xTg-AD mouse model. Egr-1 silencing 
      does not affect levels of cyclin-dependent protein kinase 5 (Cdk5), glycogen 
      synthase kinase 3beta, protein phosphatase 1, or protein phosphatase 2A, but reduces 
      p35 subunit of Cdk5. Egr-1 silencing also reduces levels of beta-secretase 1 
      (BACE-1) and BACE-1-cleaved amyloid precursor protein (APP) metabolites (secreted 
      APPbeta, C99, Abeta40, and Abeta42) but has no effect on presenilin 1 and presenilin 2. In 
      hippocampal primary neurons, Egr-1 binds to BACE-1 and p35 promoters, enhances 
      tau phosphorylation, activates Cdk5 and BACE-1, and accelerates amyloidogenic APP 
      processing. Blocking Cdk5 action blocks Egr-1-induced tau phosphorylation but has 
      no effect on BACE-1 activation and amyloidogenic APP processing. Blocking BACE-1 
      action, on the other hand, blocks Egr-1-induced amyloidogenic APP processing but 
      does not affect tau phosphorylation. Egr-1 regulates tau phosphorylation and Abeta 
      synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, 
      suggesting that Egr-1 is a potential therapeutic candidate for the treatment of 
      AD.
CI  - Copyright (c) 2017 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Qin, Xike
AU  - Qin X
AD  - Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, 
      Quebec, Canada.
FAU - Wang, Yunling
AU  - Wang Y
AD  - Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, 
      Quebec, Canada.
FAU - Paudel, Hemant K
AU  - Paudel HK
AD  - Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, 
      Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, 
      Montreal, Quebec, Canada. Electronic address: hemant.paudel@mcgill.ca.
LA  - eng
PT  - Journal Article
DEP - 20170620
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (Egr1 protein, mouse)
RN  - 0 (Presenilins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
SB  - IM
MH  - Alzheimer Disease/genetics/*metabolism/pathology/psychology
MH  - Amyloid Precursor Protein Secretases/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/metabolism
MH  - Cognition/*physiology
MH  - Cyclin-Dependent Kinase 5/metabolism
MH  - Disease Models, Animal
MH  - Early Growth Response Protein 1/genetics/*metabolism
MH  - Gene Silencing
MH  - Hippocampus/*metabolism/pathology
MH  - Maze Learning/*physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurofibrillary Tangles/genetics/metabolism/pathology
MH  - Neurons/metabolism/pathology
MH  - Phosphorylation
MH  - Plaque, Amyloid/genetics/metabolism/pathology/psychology
MH  - Presenilins/metabolism
MH  - RNA, Small Interfering
MH  - tau Proteins/metabolism
EDAT- 2017/06/24 06:00
MHDA- 2017/09/13 06:00
CRDT- 2017/06/23 06:00
PHST- 2017/03/09 00:00 [received]
PHST- 2017/04/06 00:00 [accepted]
PHST- 2017/06/24 06:00 [pubmed]
PHST- 2017/09/13 06:00 [medline]
PHST- 2017/06/23 06:00 [entrez]
AID - S0002-9440(17)30304-8 [pii]
AID - 10.1016/j.ajpath.2017.04.018 [doi]
PST - ppublish
SO  - Am J Pathol. 2017 Aug;187(8):1828-1847. doi: 10.1016/j.ajpath.2017.04.018. Epub 
      2017 Jun 20.