UC San Diego

Amyloid disorders such as Alzheimer's disease (AD) involve the aggregation of secreted proteins. However, it is largely unclear how secretory-pathway proteins contribute to amyloid formation. We developed a systems biology framework integrating expression data with protein-protein interaction networks to estimate a tissue's fitness for producing specific secreted proteins and analyzed the fitness of the secretory pathway of various brain regions and cell types for synthesizing the AD-associated amyloid precursor protein (APP). While key amyloidogenic pathway components were not differentially expressed in AD brains, we found Aβ deposition correlates with systemic down- and upregulation of the secretory-pathway components proximal to APP and amyloidogenic secretases, respectively, in AD. Our analyses suggest that perturbations from three AD risk loci cascade through the APP secretory-support network and into the endocytosis pathway, connecting amyloidogenesis to dysregulation of secretory-pathway components supporting APP and suggesting novel therapeutic targets for AD. A record of this paper's transparent peer review process is included in the supplemental information.