Abstract
Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer’s disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.
Highlights
Alzheimer’s disease (AD) is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit AD neuropathology in the absence of clinically detectable cognitive decline [1,2,3,4,5,6]
Our membrane-enrichment strategy generates a fraction with as much as 2.5-fold enrichment of proteins associated with the cell surface and organelle membranes, e.g., mitochondria, transport vesicles, endoplasmic reticulum, and synapses [19,20,21]
We applied this membrane-enrichment protocol to eighteen enrichment strategy generates a fraction with as much as 2.5-fold enrichment of proteins associated with the cell surface and organelle membranes, e.g., mitochondria, transport vesicles, endoplasmic reticulum, and synapses [19,20,21]
Summary
Alzheimer’s disease (AD) is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit AD neuropathology in the absence of clinically detectable cognitive decline [1,2,3,4,5,6] This preclinical stage of disease presents a critical window for early detection and intervention. Using post-mortem cortical samples from control, AsymAD, and AD subjects, we identified disease-specific modules of co-expressed proteins, several of which demonstrated notable changes in preclinical disease. These disease-associated co-expression modules were preserved across different
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