Proteomic analysis of the brain tissues from a transgenic mouse model of amyloid ¦Â oligomers

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• 作者：Masaoki Takano ; Kouji Maekura ; Mieko Otani ; Keiji Sano ; Tooru Nakamura-Hirota ; Shogo Tokuyama ; Kyong Son Min ; Takami Tomiyama ; Hiroshi Mori ; Shogo Matsuyama
• 关键词：Proteome ; Amyloid ¦Â oligomers ; Alzheimer&rsquo ; s disease ; Hippocampus ; Cortex ; Phosphoproteome
• 刊名：Neurochemistry International
• 出版年：2012
• 出版时间：August, 2012
• 年：2012
• 卷：61
• 期：3
• 页码：347-355
• 全文大小：639 K

文摘

Amyloid ¦Â (A¦Â) oligomers are presumed to be one of the causes of Alzheimer¡¯s disease (AD). Previously, we identified the E693¦¤ mutation in amyloid precursor protein (APP) in patients with AD who displayed almost no signals of amyloid plaques in amyloid imaging. We generated APP-transgenic mice expressing the E693¦¤ mutation and found that they possessed abundant A¦Â oligomers from 8 months of age but no amyloid plaques even at 24 months of age, indicating that these mice are a good model to study pathological effects of A¦Â oligomers. To elucidate whether A¦Â oligomers affect proteome levels in the brain, we examined the proteins and phosphoproteins for which levels were altered in 12-month-old APP_E693¦¤-transgenic mice compared with age-matched non-transgenic littermates. By two-dimensional gel electrophoresis (2DE) followed by staining with SYPRO Ruby and Pro-Q Diamond and subsequent mass spectrometry techniques, we identified 17 proteins and 3 phosphoproteins to be significantly changed in the hippocampus and cerebral cortex of APP_E693¦¤-transgenic mice. Coactosin like-protein, SH3 domain-bind glutamic acid-rich-like protein 3 and astrocytic phosphoprotein PEA-15 isoform 2 were decreased to levels less than 0.6 times those of non-transgenic littermates, whereas dynamin, profilin-2, vacuolar adenosine triphosphatase and creatine kinase B were increased to levels more than 1.5 times those of non-transgenic littermates. Furthermore, 2DE Western Blotting validated the changed levels of dynamin, dihydropyrimidinase-related protein 2 (Dpysl2), and coactosin in APP_E693¦¤-transgenic mice. Glyoxalase and isocitrate dehydrogenase were increased to levels more than 1.5 times those of non-transgenic littermates. The identified proteins could be classified into several groups that are involved in regulation of different cellular functions, such as cytoskeletal and their interacting proteins, energy metabolism, synaptic component, and vesicle transport and recycling. These findings indicate that A¦Â oligomers altered the levels of some proteins and phosphoproteins in the hippocampus and cerebral cortex, which could illuminate novel therapeutic avenues for the treatment of AD.