Original Article

Exp Neurobiol 2019; 28(3): 390-403

Published online June 26, 2019

© The Korean Society for Brain and Neural Sciences

Memantine Improves Cognitive Function and Alters Hippocampal and Cortical Proteome in Triple Transgenic Mouse Model of Alzheimer's Disease

Xinhua Zhou1,†, Liang Wang2,†, Wei Xiao3, Zhiyang Su4, Chengyou Zheng4, Zaijun Zhang4, Yuqiang Wang4, Benhong Xu5, Xifei Yang5*, and Maggie Pui Man Hoi1*

1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.

2Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510000, China.

3College of Letters & Science, University of Wisconsin-Madison, Madison, WI 53706, USA.

4Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510000, China.

5Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen 518000, China.

Correspondence to: *To whom correspondence should be addressed.
Xifei Yang, TEL: 86-0755-2550-8584, FAX: 86-0755-2550-8584, e-mail:
Maggie Pui Man Hoi, TEL: 853-8822-4876, FAX: 853-2884-1358, e-mail:
These authors contributed equally to this work.

Received: February 23, 2019; Revised: May 1, 2019; Accepted: May 6, 2019

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.

Graphical Abstract

Keywords: Alzheimer's disease (AD), Memantine, Proteomic, MARK2