Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice.
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.
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
M Y
MY
Liu
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
S
S
Wang
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
W F
WF
Yao
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
Z J
ZJ
Zhang
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
X
X
Zhong
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
L
L
Sha
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China.
M
M
He
Laboratory Animal Center, China Medical University, Shenyang, PR China.
Z H
ZH
Zheng
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, PR China. Electronic address: minjie_wei@163.com.
M J
MJ
Wei
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D065853:Spatial Learning / Q000187:drug effects* / Q000502:physiology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000715470:MAS1 protein, human; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D000090063:Proto-Oncogene Mas; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C075222:amyloid beta-protein (1-42); D020932:Nerve Growth Factor; D020917:Receptor, trkA; D008559:Memantine
APP/PS1 transgenic mice; TrkA receptor; cognitive deficit; memantine; nerve growth factor; p75 neurotrophin receptor