Quantitative mass spectrometry suggests beta‐synuclein as promising blood marker for synaptic degeneration in Alzheimer's disease

AbstractOur understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

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P2-077: Identification of potential modifiers of Alzheimer's disease pathology by quantitative mass spectrometry and drosophila genetics

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.06.614 ◽

2015 ◽

Vol 11 (7S_Part_11) ◽

pp. P512-P513

Author(s):

Benito D. Minjarez ◽

Maria Luz Valero ◽

Karla Grisel Calderon-Gonzalez ◽

Maria Esther Herrera-Aguirre ◽

Maria Luisa Labra-Barrios ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quantitative Mass Spectrometry ◽

Drosophila Genetics

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Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer’s Disease

Journal of Proteome Research ◽

10.1021/acs.jproteome.9b00824 ◽

2020 ◽

Vol 19 (3) ◽

pp. 1310-1318 ◽

Cited By ~ 1

Author(s):

Patrick Oeckl ◽

Steffen Halbgebauer ◽

Sarah Anderl-Straub ◽

Christine A. F. von Arnim ◽

Janine Diehl-Schmid ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Marker

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Application of mass spectrometry-based chromatographic technologies in the diagnosis of Alzheimer’s disease

Chinese Journal of Chromatography ◽

10.3724/sp.j.1123.2011.00293 ◽

2011 ◽

Vol 29 (4) ◽

pp. 293-297

Author(s):

Dingqian WANG ◽

Guizhong XIN ◽

Ziqi SHI ◽

Jun CHEN ◽

Ping LI

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease

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Mechanistic Insights into Alzheimer’s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways

Biomedicines ◽

10.3390/biomedicines9030298 ◽

2021 ◽

Vol 9 (3) ◽

pp. 298

Author(s):

Raúl González-Domínguez ◽

Álvaro González-Domínguez ◽

Ana Sayago ◽

Juan Diego González-Sanz ◽

Alfonso María Lechuga-Sancho ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Pathways ◽

Gas Chromatography Mass Spectrometry ◽

Liquid Chromatography Mass Spectrometry ◽

Chromatography Mass Spectrometry ◽

Multiple Primary ◽

Human Disorders ◽

Direct Mass Spectrometry

Hydrophilic metabolites are closely involved in multiple primary metabolic pathways and, consequently, play an essential role in the onset and progression of multifactorial human disorders, such as Alzheimer’s disease. This review article provides a comprehensive revision of the literature published on the use of mass spectrometry-based metabolomics platforms for approaching the central metabolome in Alzheimer’s disease research, including direct mass spectrometry, gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography-mass spectrometry, and capillary electrophoresis-mass spectrometry. Overall, mounting evidence points to profound disturbances that affect a multitude of central metabolic pathways, such as the energy-related metabolism, the urea cycle, the homeostasis of amino acids, fatty acids and nucleotides, neurotransmission, and others.

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Experimental Synaptic Degeneration as a Model for the Pathogenesis of Alzheimer’s Disease: Monoclonal Antibodies and a Protein Kinase Inhibitor Block Synapse Formation and Maintenance Between Cultured CNS Neurons

Basic, Clinical, and Therapeutic Aspects of Alzheimer’s and Parkinson’s Diseases - Advances in Behavioral Biology ◽

10.1007/978-1-4684-5844-2_30 ◽

1990 ◽

pp. 153-156

Author(s):

Yoichiro Kuroda ◽

Kazuo Kobayashi ◽

Kazuyo Muramoto ◽

Akihiko Ogura ◽

Yoshihisa Kudo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Monoclonal Antibodies ◽

Protein Kinase ◽

Synapse Formation ◽

Kinase Inhibitor ◽

Protein Kinase Inhibitor ◽

Cns Neurons ◽

Synaptic Degeneration

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Total ApoE and ApoE4 Isoform Assays in an Alzheimer's Disease Case-control Study by Targeted Mass Spectrometry (n = 669): A Pilot Assay for Methionine-containing Proteotypic Peptides

Molecular & Cellular Proteomics ◽

10.1074/mcp.m112.018861 ◽

2012 ◽

Vol 11 (11) ◽

pp. 1389-1403 ◽

Cited By ~ 53

Author(s):

Romain Simon ◽

Marion Girod ◽

Catherine Fonbonne ◽

Arnaud Salvador ◽

Yohann Clément ◽

...

Keyword(s):

Mass Spectrometry ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Case Control Study ◽

Case Control ◽

Performic Acid ◽

Protein Levels ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Control Study

Allelic polymorphism of the apolipoprotein E (ApoE) gene (ApoE ε2, ApoE ε3 and ApoE ε4 alleles) gives rise to three protein isoforms (ApoE2, ApoE3 and ApoE4) that differ by 1 or 2 amino acids. Inheritance of the ApoE ε4 allele is a risk factor for developing Alzheimer's disease (AD). The potential diagnostic value of ApoE protein levels in biological fluids (i.e. cerebrospinal fluid, plasma and serum) for distinguishing between AD patients and healthy elderly subjects is subject to great controversy. Although a recent study reported subnormal total ApoE and ApoE4 levels in the plasma of AD patients, other studies have found normal or even elevated protein levels (versus controls). Because all previously reported assays were based on immunoenzymatic techniques, we decided to develop an orthogonal assay based on targeted mass spectrometry by tracking (i) a proteotypic peptide common to all ApoE isoforms and (ii) a peptide that is specific for the ε4 allele. After trypsin digestion, the ApoE4-specific peptide contains an oxidation-prone methionine residue. The endogenous methionine oxidation level was evaluated in a small cohort (n = 68) of heterozygous ε3ε4 carriers containing both healthy controls and AD patients. As expected, the proportion of oxidized residues varied from 0 to 10%, with an average of 5%. We therefore developed a standardized strategy for the unbiased, absolute quantification of ApoE4, based on performic acid oxidization of methionine. Once the sample workflow had been thoroughly validated, it was applied to the concomitant quantification of total ApoE and ApoE4 isoform in a large case-control study (n = 669). The final measurements were consistent with most previously reported ApoE concentration values and confirm the influence of the different alleles on the protein expression level. Our results illustrate (i) the reliability of selected reaction monitoring-based assays and (ii) the value of the oxidization step for unbiased monitoring of methionine-containing proteotypic peptides. Furthermore, a statistical analysis indicated that neither total ApoE and ApoE4 levels nor the ApoE/ApoE4 ratio correlated with the diagnosis of AD. These findings reinforce the conclusions of previous studies in which plasma ApoE levels had no obvious clinical significance.

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