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 Kumar
Yarbro Jay M.
Han Xian
Lutz Brianna M.
Rao Shuquan
Jiao Yun
Sifford Jeffrey M.
Han Jonghee
Wang Minghui
Tan Haiyan
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


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.