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Memantine Improves Cognitive Function and Alters Hippocampal and Cortical Proteome in Triple Transgenic Mouse Model
Xinhua Zhou1, Liang Wang2, Wei Xiao3
1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.
Abstract:
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.
Insights
Memantine treatment improved cognitive function in an Alzheimer's disease mouse model by altering protein levels in the brain. This study reveals complex proteomic changes in the hippocampus and cerebral cortex, offering new insights into Alzheimer's disease mechanisms.
Area of Science:
- Neuroscience
- Proteomics
- Pharmacology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline.
- Memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is used to manage AD symptoms.
- The specific proteomic alterations induced by memantine in AD models remain largely uncharacterized.
Purpose of the Study:
- To investigate the proteomic changes in the hippocampus and cerebral cortex of a 3xTg-AD mouse model following memantine treatment.
- To evaluate the impact of memantine on learning and memory in this AD mouse model.
- To identify specific proteins and biological pathways modulated by memantine in the AD brain.
Main Methods:
- Treatment of 8-month-old 3xTg-AD mice with memantine (5 mg/kg/bid) for 4 months.
- Behavioral assessments including step-down passive avoidance, novel object recognition, and Morris water maze tests.
- Quantitative proteomic analysis of hippocampal and cerebral cortex tissues, followed by bioinformatics analysis.
Main Results:
- Memantine significantly improved learning and memory retention in 3xTg-AD mice.
- Proteomic analysis identified numerous proteins associated with AD abnormalities in both brain regions.
- Memantine altered the expression of 233 proteins in the hippocampus and 342 proteins in the cerebral cortex, with distinct up- and down-regulated proteins identified in each region.
- Bioinformatics analysis revealed memantine modulated pathways related to cytoskeleton, ErbB signaling, axon guidance, ribosome, calcium, and MAPK signaling.
Conclusions:
- Memantine treatment enhances cognitive function in a mouse model of Alzheimer's disease.
- Memantine induces significant and region-specific proteomic alterations in the brain, with a greater impact observed in the cerebral cortex compared to the hippocampus.
- These findings provide novel insights into the complex molecular mechanisms underlying memantine's therapeutic effects in Alzheimer's disease.