Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression

Bai, Bing; Wang, Xusheng; Li, Yuxin; Chen, Ping Chung; Yu, Kaiwen; Dey, Kaushik; Yarbro, Jay M.; Han, Xian; Lutz, Brianna Marie; Rao, Shuquan; Jiao, Yun; Sifford, Jeffrey M.; Han, Jonghee; Wang, Minghui; Tan, Haidong; Shaw, Timothy I.; Cho, Ji Hoon; Zhou, Suiping; Wang, Hong; Niu, Mingming; Mancieri, Ariana; Messler, Kaitlynn A.; Sun, Xiaojun; Wu, Zhiping; Pagala, Vishwajeeth; High, Anthony A.; Bi, Wenjian; Zhang, Hui; Chi, Hongbo; Haroutunian, Vahram; Zhang, Bin; Beach, Thomas G.; Yu, Gang; Peng, Junmin

doi:10.1016/j.neuron.2020.04.031

Cited by 65 publications

(86 citation statements)

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“…Remarkably, Clusterin was significantly decreased in the 5XFAD mice, which contrasts the results of previous research (Bai et al, 2020). Clusterin levels were higher in AD patients than in controls, especially in regions with the greatest abundance of Aβ, facilitating the development of AD (Miners et al, 2017).…”

Section: Further Validation Of Urinary Exosomal Proteins Showed Signicontrasting

confidence: 99%

“…The corresponding immunoblotting density of these proteins is shown in Figures 6B-L, 7B-L. Remarkably, according to the above three methods, HEXB, a lysosome and/or autophagy pathway protein, was significantly increased in the urinary exosomal proteins compared with the control group, consistent with the differential expression of HEXB in the brain of 5XFAD mice (Bai et al, 2020). Additionally, four proteins, AOAH, Clustrin, Ly86, and Preol, showed the same trend, with significant differences in the proteome and WB analyses.…”

Section: Identification Of Differentially Expressed Proteins By Multisupporting

confidence: 66%

“…Importantly, a recent report indicated that three proteins, Aβ, TREM2 and Clusterin, display an early increase in patients with severe Aβ pathology but no detectable cognitive defects (Nelson et al, 2012) and in patients with mild cognitive impairment, with continuous accumulation in AD. These proteins are enriched in 12 signaling pathways, including the cytoskeleton and extracellular matrix, membrane transport, and synaptic function (Bai et al, 2020). As a heterodimeric glycoprotein, Clusterin is more abundant in the CSF of some neurodegenerative disease patients than in healthy controls, and could thus serve as a potential biomarker to differentiate Parkinson's disease from dementia with Lewy bodies (Vranová et al, 2016).…”

Section: Further Validation Of Urinary Exosomal Proteins Showed Signimentioning

confidence: 99%

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Comprehensive Proteomic Profiling of Urinary Exosomes and Identification of Potential Non-invasive Early Biomarkers of Alzheimer’s Disease in 5XFAD Mouse Model

Song

Zhang

et al. 2020

Front. Genet.

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Background: Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by irreversible progressive cognitive deficits. Identification of candidate biomarkers, before amyloid-β-plaque deposition occurs, is therefore of great importance for early intervention of AD. Objective: To investigate the potential non-invasive early biomarkers of AD in 5XFAD mouse model, we investigate the proteome of urinary exosomes present in 1-monthold (before amyloid-β accumulation) 5XFAD mouse models and their littermate controls. Another two groups of 2 and 6 months-old urinary samples were collected for monitoring the dynamic change of target proteins during AD progression. Methods: Proteomic, bioinformatics analysis, multiple reaction monitoring (MRM), western blotting (WB) or ELISA were performed for analyzing these urinary exosomes. Results: A total of 316 proteins including 44 brain cell markers were identified using liquid chromatography tandem mass spectrometry. Importantly, 18 proteins were unique to the 5XFAD group. Eighty-eight proteins including 11 brain cell markers were differentially expressed. Twenty-two proteins were selected to be verified by WB. Furthermore, based on an independent set of 12 urinary exosomes samples, five in these proteins were further confirmed significant difference. Notably, Annexin 2 and Clusterin displayed significant decreased in AD model during the course detected by ELISA. AOAH, Clusterin, and Ly86 are also brain cell markers that were first reported differential expression in urinary exosomes of AD model.

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Section: Further Validation Of Urinary Exosomal Proteins Showed Signicontrasting

confidence: 99%

Section: Identification Of Differentially Expressed Proteins By Multisupporting

confidence: 66%

Section: Further Validation Of Urinary Exosomal Proteins Showed Signimentioning

confidence: 99%

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Comprehensive Proteomic Profiling of Urinary Exosomes and Identification of Potential Non-invasive Early Biomarkers of Alzheimer’s Disease in 5XFAD Mouse Model

Song

Zhang

et al. 2020

Front. Genet.

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“…332 A recently-conducted comprehensive study combining mass spectrometry-based proteomics and integrated multi-omics using samples from AD patients and 5XFAD AD mice described the upregulation of four proteins involved in iron homeostasis. 333 Although none of the upregulated proteins described above were identified in this particular study, the expression of Lf, the iron-binding protein, and STEAP3, the endosomal ferroreductase that converts insoluble Fe 3+ to soluble Fe 2+ were among the genes that are substantially elevated in both AD mice and patients. 333 Upregulation of these genes would increase cytosolic accumulation of Fe 2 .…”

Section: Deregulated Iron Homeostasis and Neurodegenerative Disordersmentioning

confidence: 61%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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“…Using large-scale genome-wide association studies (GWAS), twenty loci showed genome-wide significant association with AD, among which 11 were newly discovered [9]. A recent study using deep profiling of proteome and phosphoproteome prioritized proteins and pathways associated with AD, and it was shown that protein changes and their corresponding RNA levels only partially coincide [10]. The large amount of multiomics data and recent advances in network-based methodologies for drug repurposing today present unprecedented opportunities for accelerating target identification for drug discovery for AD.…”

Section: Introductionmentioning

confidence: 99%

AlzGPS: a genome-wide positioning systems platform to catalyze multi-omics for Alzheimer’s drug discovery

et al. 2021

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Background Recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor. Methods In this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer’s Drug Discovery, https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention and treatment for AD. Results Via AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecule profiles underlying AD pathogenesis (e.g., early vs. late stage and tau or amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we provided possible treatment information from ~ 3000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated nearly 300 literature references for high-confidence drug candidates; (5) we included information from over 1000 AD clinical trials noting drug’s mechanisms-of-action and primary drug targets, and linking them to our integrated multi-omics view for targets and network analysis results for the drugs; (6) we implemented a highly interactive web interface for database browsing and network visualization. Conclusions Network visualization enabled by AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for omics-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.

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Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression

Cited by 65 publications

References 0 publications

Comprehensive Proteomic Profiling of Urinary Exosomes and Identification of Potential Non-invasive Early Biomarkers of Alzheimer’s Disease in 5XFAD Mouse Model

Comprehensive Proteomic Profiling of Urinary Exosomes and Identification of Potential Non-invasive Early Biomarkers of Alzheimer’s Disease in 5XFAD Mouse Model

Overdosing on iron: Elevated iron and degenerative brain disorders

AlzGPS: a genome-wide positioning systems platform to catalyze multi-omics for Alzheimer’s drug discovery

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