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 journalArticlepeer-review

210 Scopus citations


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 languageEnglish
Pages (from-to)975-991.e7
Issue number6
StatePublished - 18 Mar 2020


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


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