Publication
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
# Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression
This study uses mass spectrometry to profile over 14,000 proteins and 34,000 phosphosites in human brain tissue across Alzheimer's disease stages, identifying 173 protein changes distributed across 17 pathways. The researchers validate altered proteins in independent cohorts and characterize their RNA-level dependencies, while comparing brain tissue and cerebrospinal fluid proteomes to nominate biomarker candidates.
Integration with 5xFAD transgenic mice reveals 15 amyloid-beta-correlated proteins (MDK, NTN1, SMOC1, SLIT2, HTRA1) and highlights molecular differences between the mouse model and symptomatic human AD. The 5xFAD proteome shows activated autophagy and interferon response but lacks human-specific pathological features such as neurotrophic factor downregulation and synaptic protein loss. Multi-omics analysis prioritizes disease-relevant pathways including amyloid cascade, inflammation, complement, Wnt and TGF-β signaling, lipid metabolism, iron homeostasis, and membrane transport, with several amyloid-correlated proteins colocalizing with brain plaques.
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.