Owen Joshua B, Di Domenico Fabio, Sultana Rukhsana, Perluigi Marzia, Cini Chiara, Pierce William M, Butterfield D Allan
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
J Proteome Res. 2009 Feb;8(2):471-82. doi: 10.1021/pr800667a.
Alzheimer's disease (AD) is the most common type of dementia, comprising 60-80% of all reported cases, and currently affects 5.2 million Americans. AD is characterized pathologically by the accumulation of senile plaques (SPs), neurofibrillary tangles (NFTs), and synapse loss. The early stages of memory loss associated with AD have been studied in a condition known as amnestic mild cognitive impairment (MCI), arguably the earliest form of AD. In spite of extensive research across a variety of disciplines, the cause of AD remains elusive. Proteomics techniques have helped to advance knowledge about AD by identifying irregularities in protein expression and post-translational modifications (PTMs) in AD brain. Glycosylation is a less studied PTM with regards to AD and MCI. This PTM is important to study because glycosylation is involved in proper protein folding, protein anchoring to cell membranes, and the delivery of proteins to organelles, and these processes are impaired in AD. Concanavalin-A (Con-A) binds to N-linked glycoproteins, but hydrophobic sites on nonglycoproteins are also known to bind Con-A. To our knowledge, the present study is the first to examine Con-A-associated brain proteins in MCI and AD with focus on the hippocampus and inferior parietal lobule (IPL) brain regions. Proteins found in AD hippocampus with altered levels are glutamate dehydrogenase (GDH), glial fibrillary acidic protein (GFAP), tropomyosin 3 (TPM3), Rab GDP-dissociation inhibitor XAP-4 (XAP4), and heat shock protein 90 (HSP90). Proteins found with altered levels in AD IPL are alpha-enolase, gamma-enolase, and XAP-4. MCI hippocampal proteins with altered levels are dihydropyrimidase-2 (DRP2), glucose-regulated protein 78 (GRP-78), protein phosphatase related protein Sds-22 (Sds22), and GFAP and the only protein found with altered levels in MCI IPL was beta-synuclein. These results are discussed with reference to biochemical and pathological alterations in and progression of AD.
阿尔茨海默病（AD）是最常见的痴呆类型，占所有报告病例的60 - 80%，目前影响着520万美国人。AD的病理特征是老年斑（SPs）、神经原纤维缠结（NFTs）的积累以及突触丧失。与AD相关的记忆丧失早期阶段已在一种称为遗忘型轻度认知障碍（MCI）的病症中进行了研究，MCI可以说是AD的最早形式。尽管跨多个学科进行了广泛研究，但AD的病因仍然不明。蛋白质组学技术通过识别AD大脑中蛋白质表达和翻译后修饰（PTM）的异常，有助于推进对AD的认识。就AD和MCI而言，糖基化是一种研究较少的PTM。研究这种PTM很重要，因为糖基化参与蛋白质的正确折叠、蛋白质与细胞膜的锚定以及蛋白质向细胞器的转运，而这些过程在AD中受损。伴刀豆球蛋白A（Con - A）与N - 连接糖蛋白结合，但已知非糖蛋白上的疏水位点也能结合Con - A。据我们所知，本研究是首次聚焦海马体和顶下小叶（IPL）脑区，研究MCI和AD中与Con - A相关的脑蛋白。在AD海马体中发现水平改变的蛋白质有谷氨酸脱氢酶（GDH）、胶质纤维酸性蛋白（GFAP）、原肌球蛋白3（TPM3）、Rab GDP解离抑制剂XAP - 4（XAP4）和热休克蛋白90（HSP90）。在AD的IPL中发现水平改变的蛋白质有α - 烯醇化酶、γ - 烯醇化酶和XAP - 4。MCI海马体中水平改变的蛋白质有二氢嘧啶酶 - 2（DRP2）、葡萄糖调节蛋白78（GRP - 78）、蛋白磷酸酶相关蛋白Sds - 22（Sds22）和GFAP，而在MCI的IPL中发现水平改变的唯一蛋白质是β - 突触核蛋白。将结合AD的生化和病理改变及进展对这些结果进行讨论。
