A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease

Seyfried, Nicholas T.; Dammer, Eric B.; Swarup, Vivek; Nandakumar, Divya; Duong, Duc M.; Yin, Luming; Deng, Qiudong; Nguyen, Tu; Hales, Chadwick M.; Wingo, Thomas S.; Glass, Jonathan D.; Gearing, Marla; Thambisetty, Madhav; Troncoso, Juan C.; Geschwind, Daniel H.; Lah, James J.; Levey, Aĺlan I.

doi:10.1016/j.cels.2016.11.006

Cited by 406 publications

(774 citation statements)

References 61 publications

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“…These findings, and those recently published from others (Seyfried et al, 2017), raise the possibility that studying groups of co-expressed proteins might be advantageous over the study of individual proteins due to the highly complex response of various cell types to toxic Aβ…”

Section: Discussionsupporting

confidence: 63%

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

et al. 2017

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SUMMARY Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission. Analysis of the AMPA receptor (AMPAR) complex revealed specific loss of TARPγ-2, a key AMPAR trafficking protein. Expression of TARPγ-2 in hAPP transgenic mice restored of AMPA currents. This proteomic database represents a resource for the identification of protein alterations responsible for AD.

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Section: Discussionsupporting

confidence: 63%

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

et al. 2017

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“…Previously, investigations into allele-specific abundance generally focus on RNA, which is not always feasibly obtained from post-mortem human tissue and not highly correlated with protein abundance based 28 . Mass spectrometry-based proteomics has been used to test this in a limited way for common SNVs of blood proteins 46 , but more comprehensive approaches are needed, and, here, we present a pipeline for future investigations.…”

Section: Discussionmentioning

confidence: 99%

“…Each tissue sample was processed as described 28 with slight modification. Briefly, each tissue was individually weighed (approximately 0.1 g) and homogenized (Dounce homogenizer) in 500 μL of urea lysis buffer (8M urea, 50 mM Tris-HCl, pH 7.8), including both protease inhibitors (Roche) and the HALT (Pierce) phosphatase inhibitor cocktail, 0.6% (v/v).…”

Section: Methodsmentioning

confidence: 99%

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Integrating Next-Generation Genomic Sequencing and Mass Spectrometry To Estimate Allele-Specific Protein Abundance in Human Brain

Wingo¹,

Duong²,

Zhou³

et al. 2017

J. Proteome Res.

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Gene expression contributes to phenotypic traits and human disease. To date, comparatively less is known about regulators of protein abundance, which is also under genetic control and likely influences clinical phenotypes. However, identifying and quantifying allele-specific protein abundance by bottom-up proteomics is challenging since single nucleotide variants (SNVs) that alter protein sequence are not considered in standard human protein databases. To address this, we developed the GenPro software and used it to create personalized protein databases (PPDs) to identify single amino acid variants (SAAVs) at the protein level from whole exome sequencing. In silico assessment of PPDs generated by GenPro revealed only a 1% increase in tryptic search space compared to a direct translation of all human transcripts and an equivalent search space compared to the UniProtKB reference database. To identify a large unbiased number of SAAV peptides, we performed high-resolution mass spectrometry-based proteomics for two human post-mortem brain samples and searched the collected MS/MS spectra against their respective PPD. We found an average of ~117,000 unique peptides mapping to ~9,300 protein groups for each sample and of these 977 were unique variant peptides. We found that over 400 reference and SAAV peptide pairs were, on average, equally abundant in human brain by label-free ion intensity measurements and confirmed the absolute levels of three reference and SAAV peptide pairs using heavy labeled peptides standards coupled with parallel reaction monitoring (PRM). Our results highlight the utility of integrating genomic and proteomic sequencing data to identify sample-specific SAAV peptides and support the hypothesis that most alleles are equally expressed in human brain.

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“…For end of life diseases, like PD, AD, and amyotrophic lateral sclerosis (ALS), brains are readily available, and decades of pathological studies have created gold standard definitions for each disease in terms of regional and circuit atrophy and specific classes of pathological signatures, and at least for AD, a corresponding inflammatory signature is apparent in postmortem transcriptomic[60,61] and proteomic data. However psychiatric diseases with earlier onset, and that are not directly lethal (ASD, SCZ), provide substantially less opportunity for post mortem pathology to define cellular deficits.…”

Section: Introductionmentioning

confidence: 99%

Systems biology in the central nervous system: A brief perspective on essential recent advancements

Dougherty

Yang

Lake

2017

Current Opinion in Systems Biology

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As recent advances in human genetics have begun to more rapidly identify the individual genes contributing to risk of psychiatric disease, the spotlight now turns to understanding how disruption of these genes alters the brain, and thus behavior. Compared to other tissues, cellular complexity in the brain provides both a substantial challenge and a significant opportunity for systems biology approaches. Current methods are maturing that will allow for finally defining the ‘parts list’ for the functioning mouse and human brains, enabling new approaches to defining how the system goes awry in disorders of the CNS. However, the availability of tissue is certainly a challenge for systems biology of neuroscience, compared to systems biology of other tissues, where biopsy is feasible. This challenge is particularly notable for disorders caused by extremely rare genetic variants. Thus computational and systems biology approaches, as well as precise experimental models by way of genome editing, will play key roles in defining mechanisms for disorders, and their individual symptoms, across varied genetic etiologies. Here, we highlight recent progress in neurogenetics, postmortem genomics, cell-type specific profiling, and precision modeling toward defining mechanisms in disease.

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A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease

Cited by 406 publications

References 61 publications

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer’s Disease-like Pathology

Integrating Next-Generation Genomic Sequencing and Mass Spectrometry To Estimate Allele-Specific Protein Abundance in Human Brain

Systems biology in the central nervous system: A brief perspective on essential recent advancements

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