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

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

doi:10.1016/j.neuron.2019.12.015

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

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

Research output: Contribution to journal › Article › peer-review

230 Scopus citations

Abstract

Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.

Original language	English (US)
Pages (from-to)	975-991.e7
Journal	Neuron
Volume	105
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2019.12.015
State	Published - Mar 18 2020

Keywords

Alzheimer's disease
biomarker
cerebrospinal fluid
genomics
mass spectrometry
multi-omics
phosphoproteome
proteome
proteomics
systems biology

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2019.12.015

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Bai, B., Wang, X., Li, Y., Chen, P. C., Yu, K., Dey, K. K., Yarbro, J. M., Han, X., Lutz, B. M., Rao, S., Jiao, Y., Sifford, J. M., Han, J., Wang, M., Tan, H., Shaw, T. I., Cho, J. H., Zhou, S., Wang, H., ... Peng, J. (2020). Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression. Neuron, 105(6), 975-991.e7. https://doi.org/10.1016/j.neuron.2019.12.015

Bai, B, Wang, X, Li, Y, Chen, PC, Yu, K, Dey, KK, Yarbro, JM, Han, X, Lutz, BM, Rao, S, Jiao, Y, Sifford, JM, Han, J, Wang, M, Tan, H, Shaw, TI, Cho, JH, Zhou, S, Wang, H, Niu, M, Mancieri, A, Messler, KA, Sun, X, Wu, Z, Pagala, V, High, AA, Bi, W, Zhang, H, Chi, H, Haroutunian, V, Zhang, B, Beach, TG, Yu, G & Peng, J 2020, 'Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression', Neuron, vol. 105, no. 6, pp. 975-991.e7. https://doi.org/10.1016/j.neuron.2019.12.015

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title = "Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression",

abstract = "Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.",

keywords = "Alzheimer's disease, biomarker, cerebrospinal fluid, genomics, mass spectrometry, multi-omics, phosphoproteome, proteome, proteomics, systems biology",

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

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2020",

month = mar,

day = "18",

doi = "10.1016/j.neuron.2019.12.015",

language = "English (US)",

volume = "105",

pages = "975--991.e7",

journal = "Neuron",

issn = "0896-6273",

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number = "6",

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TY - JOUR

T1 - Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression

AU - Bai, Bing

AU - Wang, Xusheng

AU - Li, Yuxin

AU - Chen, Ping Chung

AU - Yu, Kaiwen

AU - Dey, Kaushik Kumar

AU - Yarbro, Jay M.

AU - Han, Xian

AU - Lutz, Brianna M.

AU - Rao, Shuquan

AU - Jiao, Yun

AU - Sifford, Jeffrey M.

AU - Han, Jonghee

AU - Wang, Minghui

AU - Tan, Haiyan

AU - Shaw, Timothy I.

AU - Cho, Ji Hoon

AU - Zhou, Suiping

AU - Wang, Hong

AU - Niu, Mingming

AU - Mancieri, Ariana

AU - Messler, Kaitlynn A.

AU - Sun, Xiaojun

AU - Wu, Zhiping

AU - Pagala, Vishwajeeth

AU - High, Anthony A.

AU - Bi, Wenjian

AU - Zhang, Hui

AU - Chi, Hongbo

AU - Haroutunian, Vahram

AU - Zhang, Bin

AU - Beach, Thomas G.

AU - Yu, Gang

AU - Peng, Junmin

PY - 2020/3/18

Y1 - 2020/3/18

N2 - Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.

AB - Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.

KW - Alzheimer's disease

KW - biomarker

KW - cerebrospinal fluid

KW - genomics

KW - mass spectrometry

KW - multi-omics

KW - phosphoproteome

KW - proteome

KW - proteomics

KW - systems biology

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UR - http://www.scopus.com/inward/citedby.url?scp=85081401963&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2019.12.015

DO - 10.1016/j.neuron.2019.12.015

M3 - Article

C2 - 31926610

AN - SCOPUS:85081401963

SN - 0896-6273

VL - 105

SP - 975-991.e7

JO - Neuron

JF - Neuron

IS - 6

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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