Publication
A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
Seyfried Nicholas T, Dammer Eric B, Swarup Vivek, Nandakumar Divya, Duong Duc M, Yin Luming, Deng Qiudong, Nguyen Tram, Hales Chadwick M, Wingo Thomas, Glass Jonathan, Gearing Marla, Thambisetty Madhav, Troncoso Juan C, Geschwind Daniel H, Lah James J, Levey Allan I
This study analyzed cortical proteins from 129 human brains to characterize molecular changes in asymptomatic and symptomatic Alzheimer's disease (AD). Using network analysis, researchers identified 16 co-expressed protein modules, ten of which correlated with AD phenotypes. Some modules overlapped with RNA co-expression networks associated with neuronal and astroglial cell types, showing altered expression even in asymptomatic AD stages, while others were protein-specific and linked to microtubule function and inflammation.
The multi-network proteomics approach, validated in an independent cohort, revealed both AD-specific and shared pathways observed in other neurodegenerative diseases. AD genetic risk loci were preferentially concentrated in glial-related modules in both proteome and transcriptome data, supporting a glial contribution to disease causality. The findings demonstrate that integration of protein and RNA networks identifies disease-specific pathways relevant to AD etiology, initiation, and progression, with proteomics capturing protein-specific changes not evident at the transcriptional level.
Abstract
Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.