@article{cb4cb5b95e4c4203a281c68d29be5fe6,
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 = "Funding Information: We thank all other members in the lab and center for technical support and discussions. This work was partially supported by NIH grants R01AG047928 (to J.P.), R01AG053987 (to J.P.), R01GM114260 (to J.P.), R01AG064909 (to G.Y. and J.P.), RF1AG057440 (to B.Z. and V.H.), U01AG046170 (to V.H. and B.Z.), R01AG057907 (to V.H. and B.Z.), R01NS079796 (to G.Y.), U24NS072026 (to T.G.B.), and P30AG019610 (to T.G.B.); the Arizona Department of Health Services (contract 211002 to T.G.B.), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 , and 1001 to T.G.B.); RF1AG057440 (to V.H. and B.Z.); and ALSAC (American Lebanese Syrian Associated Charities). The MS analysis was performed in the Center of Proteomics and Metabolomics, and the microscopy analysis was performed in the Cell and Tissue Imaging Core at St. Jude Children{\textquoteright}s Research Hospital, partially supported by NIH Cancer Center support grant P30CA021765 . Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = mar,
day = "18",
doi = "10.1016/j.neuron.2019.12.015",
language = "English",
volume = "105",
pages = "975--991.e7",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "6",
}