Dataset Information

Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (A?) as the A?-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the A?-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.

SUBMITTER: Kim DK

PROVIDER: S-EPMC6856180 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer's disease.

Kim Dong Kyu DK Han Dohyun D Park Joonho J Choi Hyunjung H Park Jong-Chan JC Cha Moon-Yong MY Woo Jongmin J Byun Min Soo MS Lee Dong Young DY Kim Youngsoo Y Mook-Jung Inhee I

Experimental & molecular medicine 20191115 11

Alzheimer's disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between pro ...[more]

PMID: 31727875

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Project description:BackgroundBlood-based protein measurement is a routine practice for detecting biomarkers in human disease. Comprehensive profiling of blood/plasma/serum proteome is a challenge due to an extremely large dynamic range, as exemplified by a small subset of highly abundant proteins. Antibody-based depletion of these abundant proteins alleviates the problem but introduces experimental variations. We aimed to establish a method for direct profiling of undepleted human serum and apply the method toward biomarker discovery for Alzheimer's disease (AD), as AD is the most common form of dementia without available blood-based biomarkers in clinic.MethodsWe present an ultra-deep analysis of undepleted human serum proteome by combining the latest 11-plex tandem-mass-tag (TMT) labeling, exhaustive two-dimensional liquid chromatography (LC/LC) fractionation (the 1st LC: 3 h for 180 fractions, and the 2nd LC: 3 h gradient per fraction), coupled with high resolution tandem mass spectrometry (MS/MS). AD (n = 6) and control (n = 5) sera were analyzed in this pilot study. In addition, we implemented a multiplexed targeted LC-MS3 method (TOMAHAQ) for the validation of selected target proteins.ResultsThe TMT-LC/LC-MS/MS platform is capable of analyzing 4826 protein components (4368 genes), covering at least 6 orders of magnitude in dynamic range, representing one of the deepest serum proteome analysis. We defined intra- and inter- group variability in the AD and control groups. Statistical analysis revealed differentially expressed proteins in AD (26 decreased and 4 increased). Notably, these altered proteins are enriched in the known pathways of mitochondria, fatty acid beta oxidation, and AGE/RAGE. Finally, we set up a TOMAHAQ method to confirm the decrease of PCK2 and AK2 in our AD samples.ConclusionsOur results show an ultra-deep serum discovery study by TMT-LC/LC-MS/MS, and a validation experiment by TOMAHAQ targeted LC-MS3. The MS-based discovery and validation methods are of general use for biomarker discovery from complex biofluids (e.g. serum proteome). This pilot study also identified deregulated proteins, in particular proteins associated with mitochondrial function in the AD serum samples. These proteins may serve as novel AD candidate biomarkers.

Project description:There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease-neuronal synapse/signaling and lysosome/stress response-were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

Dataset Information

Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer's disease.

Publications

Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer's disease.

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