PMID- 24846616
OWN - NLM
STAT- MEDLINE
DCOM- 20150209
LR  - 20231213
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 273
DP  - 2014 Jul 25
TI  - Memantine improves spatial learning and memory impairments by regulating NGF 
      signaling in APP/PS1 transgenic mice.
PG  - 141-51
LID - S0306-4522(14)00403-5 [pii]
LID - 10.1016/j.neuroscience.2014.05.011 [doi]
AB  - Memantine (MEM) is used for improving the cognitive impairments of the patients 
      suffering from Alzheimer's disease (AD) by multiple neuroprotective mechanisms. 
      However, it is still not clear whether nerve growth factor (NGF) signaling is 
      involved in the mechanisms of MEM. The present study investigated the 
      neuroprotective effects of MEM treatment on the cognitive performance and 
      amyloidosis in APP/PS1 transgenic mice, and disclosed the NGF-related mechanism 
      of MEM. We found that MEM treatment improved the cognitive performance by 
      decreasing the escape latency and path length in the navigation test, by 
      shortening the duration in target quadrant and reducing the frequency to pass 
      through the target in probe trial, and by prolonging the latency and decreasing 
      the frequencies of entering the dark compartment in passive avoidance test. The 
      over-expressions of Abeta(1-42) and amyloid precursor protein (APP) were also 
      decreased in the brains of APP/PS1 mice. Interestingly, MEM treatment improved 
      the decreased NGF levels in APP/PS1 mice. Furthermore, NGF/TrkA signaling was 
      activated by increasing the phosphorylation levels of tyrosine kinase (TrkA), 
      proto-oncogene serine/threonine-protein kinase, Raf1 (c-Raf), extracellular 
      regulated protein kinases (ERK)1/2 and cAMP-response element binding protein 
      (CREB) after MEM treatment. Simultaneously, MEM also inhibited NGF/p75(NTR) 
      signaling via decreasing the cleavage substrate of p75(NTR), increasing the JNK2 
      phosphorylation and decreasing the levels of p53 and cleaved-caspase 3. 
      Therefore, the dual-regulation on NGF signaling was attributed to the 
      improvements of cognitive deficits and Abeta depositions in APP/PS1 mice. In 
      conclusion, MEM treatment activated the NGF/TrkA signaling, and inhibited the 
      p75(NTR) signaling in APP/PS1 mice to ameliorate the behavioral deficits and 
      amyloidosis, indicating that NGF signaling was a new potential target of MEM 
      treatment for AD therapy.
CI  - Copyright (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Liu, M Y
AU  - Liu MY
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Wang, S
AU  - Wang S
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Yao, W F
AU  - Yao WF
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Zhang, Z J
AU  - Zhang ZJ
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Zhong, X
AU  - Zhong X
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Sha, L
AU  - Sha L
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - He, M
AU  - He M
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China.
FAU - Zheng, Z H
AU  - Zheng ZH
AD  - Laboratory Animal Center, China Medical University, Shenyang, PR China.
FAU - Wei, M J
AU  - Wei MJ
AD  - Department of Pharmacology, School of Pharmacy, China Medical University, 
      Shenyang, PR China. Electronic address: minjie_wei@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140515
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (APP protein, human)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (MAS1 protein, human)
RN  - 0 (Nootropic Agents)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Presenilin-1)
RN  - 0 (Proto-Oncogene Mas)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (Ngfr protein, mouse)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - W8O17SJF3T (Memantine)
SB  - IM
MH  - Alzheimer Disease
MH  - Amyloid beta-Peptides/metabolism
MH  - Amyloid beta-Protein Precursor/genetics/metabolism
MH  - Amyloidosis/*drug therapy/physiopathology
MH  - Animals
MH  - Avoidance Learning/drug effects/physiology
MH  - Brain/*drug effects/physiopathology
MH  - Cognition Disorders/*drug therapy/physiopathology
MH  - Female
MH  - Humans
MH  - Male
MH  - Memantine/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Nerve Growth Factor/metabolism
MH  - Nootropic Agents/*pharmacology
MH  - Peptide Fragments/metabolism
MH  - Presenilin-1/genetics/metabolism
MH  - Proto-Oncogene Mas
MH  - Receptor, trkA/metabolism
MH  - Receptors, Nerve Growth Factor/metabolism
MH  - Spatial Learning/*drug effects/physiology
MH  - Spatial Memory/drug effects/physiology
OTO - NOTNLM
OT  - APP/PS1 transgenic mice
OT  - TrkA receptor
OT  - cognitive deficit
OT  - memantine
OT  - nerve growth factor
OT  - p75 neurotrophin receptor
EDAT- 2014/05/23 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/05/22 06:00
PHST- 2013/12/13 00:00 [received]
PHST- 2014/05/04 00:00 [revised]
PHST- 2014/05/06 00:00 [accepted]
PHST- 2014/05/22 06:00 [entrez]
PHST- 2014/05/23 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - S0306-4522(14)00403-5 [pii]
AID - 10.1016/j.neuroscience.2014.05.011 [doi]
PST - ppublish
SO  - Neuroscience. 2014 Jul 25;273:141-51. doi: 10.1016/j.neuroscience.2014.05.011. 
      Epub 2014 May 15.