Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, so far, there are no effective measures to prevent and cure this deadly condition. Ginsenoside Rg1 (Rg1) was shown to improve behavioral abnormalities in AD; however, the potential mechanisms remain unclear. In this study, we pretreated 7-month-old 3xTg-AD mice for 6 weeks with Rg1 and evaluated the effects of Rg1 on the behaviors and the protein expression of hippocampal tissues. The behavioral tests showed that Rg1 could improve the memory impairment and ameliorate the depression-like behaviors of 3xTg-AD mice. Proteomic results revealed a total of 28 differentially expressed hippocampal proteins between Rg1-treated and nontreated 3xTg-AD mice. Among these proteins, complexin-2 (CPLX2), synapsin-2 (SYN2), and synaptosomal-associated protein 25 (SNP25) were significantly downregulated in the hippocampus of 3xTg-AD mice compared with the WT mice, and the treatment of Rg1 modulated the expression of CPLX2 and SNP25 in the hippocampus of 3xTg-AD mice. The expression of CPLX2, SYN2, and SNP25 was further validated by Western blot analysis. Taken together, we concluded that Rg1 could be a potential candidate drug to improve the behavioral deficits in AD via modulating the expression of the proteins (i.e., CPLX2, SYN2, and SNP25).

Alzheimer's disease (AD) is a devastating neurodegenerative disease accompanied by neuropsychiatric symptoms, such as anxiety and depression. The levels of melatonin decrease in brains of AD patients. The potential effect of melatonin on anxiety and depression behaviors in AD and the underlying mechanisms remain unclear. In this study, we treated 10-month-old triple transgenic mice of AD (3xTg-AD) with melatonin (10 mg/kg body weight/day) for 1 month and explored the effects of melatonin on anxiety and depression-like behaviors in 3xTg-AD mice and the protein expression of hippocampal tissues. The behavioral test showed that melatonin ameliorated anxiety and depression-like behaviors of 3xTg-AD mice as measured by open field test, elevated plus maze test, forced swimming test, and tail suspension test. By carrying out two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 46 differentially expressed proteins in hippocampus between the wild-type (WT) mice and non-treated 3xTg-AD mice. A total of 21 differentially expressed proteins were revealed in hippocampus between melatonin-treated and non-treated 3xTg-AD mice. Among these differentially expressed proteins, glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) were significantly down-regulated in hippocampus of 3xTg-AD mice compared with the WT mice. The expression of these two proteins was modulated by melatonin treatment. Our study suggested that melatonin could be used as a potential candidate drug to improve the neuropsychiatric behaviors in AD via modulating the expression of the proteins (i.e. GSTP1 and CPLX1) involved in anxiety and depression behaviors. © 2017 BioFactors, 43(4):593-611, 2017.

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Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative diseases. Apolipoprotein E4 (ApoE4) carriers account for 40% of all AD cases, emphasizing the importance of ApoE4 in the pathogenesis of AD. In the present study, we explored the changes of hippocampal proteins expression profile at the early stage (3 month-old) of APP/PS1 and ApoE4 knockin mice with the aim to find potential key pathways involved in AD progression. Proteomic analysis showed a lot of differentially expressed proteins (DEPs), 247 (137 increased and 110 decreased) and 1125 (642 increased and 484 decreased) in the hippocampus of APP/PS1 and ApoE4 mice, respectively, compared with the wild-type (WT) mice, using a cutoff of 1.2-fold change. Functional classification of DEPs revealed that these proteins mainly comprise proteins involved in acetylation, methylation, endocytosis/exocytosis, chaperone, oxidoreductase, mitochondrial, cytoskeletal, and synaptic proteins in APP/PS1 mice compared with the WT mice. Likewise in ApoE4 mice compared with the WT mice, the DEPs are mostly involved in the functions of synapses, ribosomes, mitochondria, spliceosomes, endocytosis/exocytosis, oxidative phosphorylation, and proteasomes. STRING analysis suggested that some DEPs were involved in insulin signaling and mitochondrial electron transport chain in the two mouse models. The abnormal changes of insulin signaling and mitochondrial electron transport chain were further verified by Western blot. Taken together, our study exposed the changes of hippocampal protein expression profiles at the early stage of APP/PS1 and ApoE4 knockin mice, and the change of insulin signaling and mitochondrial electron transport chain may be the key molecular processes involved in AD progression.