Dataset Information

Deep proteome profiling of hippocampus in 5xFAD mouse model

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease and characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Although extensive research was performed for Alzheimer's disease (AD) is the most common neurodegenerative disease and characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Although extensive research was performed for decades, the exact mechanisms and pathological causes of the disease still remain unknown. In order to perform comprehensive and integrative characterization of AD brain, assessment of global proteomic dynamics is required. We performed hippocampal proteome analysis to compare differentially expressed proteins in wild-type and 5XFAD model mice by label-free LC-MS. decades, the exact mechanisms and pathological causes of the disease still remain unknown. In order to perform comprehensive and integrative characterization of AD brain, assessment of global proteomic dynamics is required. We performed hippocampal proteome analysis to compare differentially expressed proteins in wild-type and 5XFAD model mice by label-free LC-MS.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Dohyun Han

LAB HEAD: Dohyun Han

PROVIDER: PXD012238 | Pride | 2020-05-26

REPOSITORIES: Pride

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Publications

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:Alzheimer's Disease (AD) is a devastating neurodegenerative disorder affecting approximately 4 million people in the U.S. alone. AD is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. These pathological markers are thought to be responsible for the massive cortical neurodegeneration and concomitant loss of memory, reasoning, and often aberrant behaviors that are seen in patients with AD. Understanding the molecular mechanisms whereby these histopathological markers develop will greatly enhance our understanding of AD development and progression. A clearer understanding of the mechanisms underlying neurofibrillary tangle formation specifically may help to clarify the basis for dementia of AD as well as the dementias associated with other diseases that are collectively referred to as "tauopathies."; To expression profile both neurons containing neurofibrillary tangles and normal neurons from the entorhinal cortex of 10 mid-stage AD cases. The gene expression profile of neurons that contain neurofibrillary tangles will differ from the expression profile of histopathologically normal neurons from the same patient and from the same brain region. Some of these differences will be informative as to the mechanisms of tangle formation. Experiment Overall Design: First use laser capture microdissection to select 1000 neurons bearing neurofibrillary tangles and 1000 normal neurons from the layer 2 stellate island neurons of the entorhinal cortex of 10 mid-stage AD cases. Second, to isolate the RNA from these captured neurons, perform double round linear amplification and hybridize the labeled cRNA to affymetrix U133A arrays. Third, to use paired, permutational t-tests to analyze the microarray data to select tangle-specific differences in gene expression. For the purposes of submitting this proposal, a value of 1 ug of RNA was entered due to web site constraints on values placed in that field. However, all samples are from LCM captured cells and the actual RNA yield is likely closer to 100 pg.

Project description:Along with the two hallmark pathologies—intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques—transcriptional studies suggest that Alzheimer's disease (AD) results from dysfunction of many cellular pathways including synaptic transmission, cytoskeletal dynamics, and apoptosis. While these studies consistently point to the same pathways involved in AD, there is no consensus on which genes in each pathway are disease-relevant, much less on whether these genes play causative roles or are downstream effects of disease progression. To address these issues, we have performed a large-scale transcriptional analysis in brain of individuals with advanced AD and non-demented controls, focusing specifically on CA1 and the relatively less affected CA3. For comparisons between regions and across disease status, we find consistency in both pathway enrichment as well as specific differentially expressed genes across several studies. Furthermore, genes that show decreased expression with AD progression also tend to show enrichment in CA3 (and vice versa), suggesting that transcription levels in a region may reflect that region's vulnerability to disease. In particular, we find several strong candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. We have also applied weighted gene coexpression network analysis (WGCNA) to explore the pathophysiology of AD from a systems perspective, finding modules for major cell types, which each show distinct disease-relevant expression patterns. In particular, a microglial module shows increased expression in the brain of non-demented controls harboring early NFT pathology, suggesting that microglial activation is an early event in AD progression. Total RNA obtained from 60um sections of frozen human hippocampus was collected using scalpel dissection. Control and AD brains were matched for all non-disease characteristics as closely as possible. CA1 and CA3 dissections for a given individual were taken from the same section. Several region- and disease-related comparisons were performed.

Dataset Information

Deep proteome profiling of hippocampus in 5xFAD mouse model

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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