Dataset Information

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

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.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6614075 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Zhou Xinhua X Wang Liang L Xiao Wei W Su Zhiyang Z Zheng Chengyou C Zhang Zaijun Z Wang Yuqiang Y Xu Benhong B Yang Xifei X Hoi Maggie Pui Man MPM

Experimental neurobiology 20190626 3

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) fo ...[more]

PMID: 31308798

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Project description:Alzheimer's disease (AD), one of the most common neurodegenerative diseases, has no effective treatment. We studied the potential effects of tetramethylpyrazine (TMP), an alkaloid in the rhizome of Ligusticum chuanxiong Hort. used in Traditional Chinese Medicine (chuānxiong) to treat ischemic stroke, on AD progression in two AD mouse models. Eight-month-old 3xTg-AD mice received TMP treatment (10 mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10 mg/kg/d) for 2 months. Behavioral tests, including step-down passive avoidance (SDA), new object recognition (NOR), Morris water maze (MWM), and Contextual fear conditioning test showed that TMP significantly improved the learning and memory of the two AD-transgenic mice. In addition, TMP reduced beta-amyloid (Aß) levels and tau phosphorylation (p-tau). Venny map pointed out that 116 proteins were commonly changed in 3xTg mice vs. wild type (WT) mice and TMP-treated mice vs. -untreated mice. The same 130 proteins were commonly changed in APP/PS1 mice vs. WT mice and TMP-treated mice vs. -untreated mice. The functions of the common proteins modified by TMP in the two models were mainly involved in mitochondrial, synaptic, cytoskeleton, ATP binding, and GTP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in the mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap, and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation (OXPHOS). Western-blot analysis confirmed that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, we demonstrated that TMP treatment changed the hippocampal proteome, reduced AD pathology, and reduced cognitive impairment in the two AD models. The changes might be associated with modification of the mitochondrial protein profile by TMP. The results of the study suggest that TMP can improve the symptoms of AD.

Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far. Methods: In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-? (A?) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of A? and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of A? deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry. Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal A?, extracellular diffuse A? deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both A? deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing A? deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3×Tg-AD mice. Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both A? and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications.

Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. So far, there is no effective treatment for this condition. Tetramethylpyrazine (TMP) is an alkaloid extracted from traditional Chinese medicine chuanxiong, which is mainly used in the treatment of ischemic stroke some related diseases. In this study, we studied the potential effects of TMP on AD progression by using two AD mouse models. 8-month-old 3xTg-AD mice received TMP treatment (10mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10mg/kg/d) for 2 months. The behavioral tests by step-down passive avoidance test (SDA), new object recognition (NOR) and Morris water maze (MWM) showed that TMP significantly improved the learning and memory impairment of two AD transgenic mice. In addition, TMP reduced Aß levels and tau phosphorylation. Venny analysis showed that 116 differentially expressed proteins were commonly changed in 3xTg mice vs WT mice and TMP treated mice vs untreated mice. The same, 130 differentially expressed proteins were commonly changed in APP/PS1 mice vs WT mice and TMP treated mice vs untreated mice. The functions of the common proteins modified by TMP in the two models were mainly related to mitochondrial function, synaptic function, cytoskeleton, GTP binding, ATP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation of (OXPHOS). Western-blot further validated that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, our study demonstrated that TMP improved the cognitive impairment and AD-like pathology, and modified hippocampal proteome in the two AD mice models. The improvement of the behavioral and pathology might be associated with modification of mitochondrial protein profile by TMP. Our study suggested that TMP had the potential for the treatment of AD.

Project description:Alzheimer's disease (AD) causes progressive age-related defects in memory and cognitive function and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Here we examine large-scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer's disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes ("miniscopes") on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3-6.5 months old) and old (18-21 months old) ages. During open-field exploration, 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. The spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotor speed significantly modulates the amplitude of hippocampal neural calcium ensemble activities to a greater extent in 3xTg-AD mice during open field exploration. Our data offer new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model and provide strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.

Dataset Information

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

Publications

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

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