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Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice.
Neuroscience 2014; 273:141-51N

Abstract

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 Aβ(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 Aβ 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.

Authors+Show Affiliations

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.Laboratory Animal Center, China Medical University, Shenyang, PR China.Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China. Electronic address: minjie_wei@163.com.

Pub Type(s)

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

Language

eng

PubMed ID

24846616

Citation

Liu, M Y., et al. "Memantine Improves Spatial Learning and Memory Impairments By Regulating NGF Signaling in APP/PS1 Transgenic Mice." Neuroscience, vol. 273, 2014, pp. 141-51.
Liu MY, Wang S, Yao WF, et al. Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice. Neuroscience. 2014;273:141-51.
Liu, M. Y., Wang, S., Yao, W. F., Zhang, Z. J., Zhong, X., Sha, L., ... Wei, M. J. (2014). Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice. Neuroscience, 273, pp. 141-51. doi:10.1016/j.neuroscience.2014.05.011.
Liu MY, et al. Memantine Improves Spatial Learning and Memory Impairments By Regulating NGF Signaling in APP/PS1 Transgenic Mice. Neuroscience. 2014 Jul 25;273:141-51. PubMed PMID: 24846616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice. AU - Liu,M Y, AU - Wang,S, AU - Yao,W F, AU - Zhang,Z J, AU - Zhong,X, AU - Sha,L, AU - He,M, AU - Zheng,Z H, AU - Wei,M J, Y1 - 2014/05/15/ PY - 2013/12/13/received PY - 2014/05/04/revised PY - 2014/05/06/accepted PY - 2014/5/22/entrez PY - 2014/5/23/pubmed PY - 2015/2/11/medline KW - APP/PS1 transgenic mice KW - TrkA receptor KW - cognitive deficit KW - memantine KW - nerve growth factor KW - p75 neurotrophin receptor SP - 141 EP - 51 JF - Neuroscience JO - Neuroscience VL - 273 N2 - 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 Aβ(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 Aβ 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. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24846616/Memantine_improves_spatial_learning_and_memory_impairments_by_regulating_NGF_signaling_in_APP/PS1_transgenic_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00403-5 DB - PRIME DP - Unbound Medicine ER -