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Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects.

ABSTRACT: Phosphorylation on tyrosine, threonine and serine residues represents one of the most important post-translational modifications and is a key regulator of cellular signaling of multiple biological processes that require a strict control by protein kinases and protein phosphatases. Abnormal protein phosphorylation has been associated with several human diseases including Alzheimer's disease (AD). One of the characteristic hallmarks of AD is the presence of neurofibrillary tangles, composed of microtubule-associated, abnormally hyperphosphorylated tau protein. However, several others proteins showed altered phosphorylation levels in AD suggesting that deregulated phosphorylation may contribute to AD pathogenesis. Phosphoproteomics has recently gained attention as a valuable approach to analyze protein phosphorylation, both in a quantitative and a qualitative way. We used the fluorescent phosphospecific Pro-Q Diamond dye to identify proteins that showed alterations in their overall phosphorylation in the hippocampus of AD vs. control (CTR) subjects. Significant changes were found for 17 proteins involved in crucial neuronal process such as energy metabolism or signal transduction. These phosphoproteome data may provide new clues to better understand molecular pathways that are deregulated in the pathogenesis and progression of AD.

SUBMITTER: Di Domenico F

PROVIDER: S-EPMC3119855 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects.

Di Domenico Fabio F Sultana Rukhsana R Barone Eugenio E Perluigi Marzia M Cini Chiara C Mancuso Cesare C Cai Jian J Pierce William M WM Butterfield D Allan DA

Journal of proteomics 20110413 7

Phosphorylation on tyrosine, threonine and serine residues represents one of the most important post-translational modifications and is a key regulator of cellular signaling of multiple biological processes that require a strict control by protein kinases and protein phosphatases. Abnormal protein phosphorylation has been associated with several human diseases including Alzheimer's disease (AD). One of the characteristic hallmarks of AD is the presence of neurofibrillary tangles, composed of mic ...[more]

PMID: 21515431

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Project description:BackgroundMicroglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometry methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally relevant molecular insights that are not provided by transcriptomics. However, comprehensive proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed.MethodsWe performed quantitative mass spectrometry based proteomic analyses of purified CD11b+ acutely-isolated microglia from adult (6 mo) mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer's disease [AD]). Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains.ResultsOf 4133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized, suggesting a role for Apoe in phagocytic clearance of Aβ.ConclusionsWe report a comprehensive proteomic study of adult mouse microglia derived from acute neuroinflammation and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identify novel roles for microglial proteins in human neurodegeneration.

Project description: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.

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Dataset Information

Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects.

Publications

Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects.

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