biostudies-literatureKuo CCNIA NIH HHSNIGMS NIH HHS873-884.e4https://www.ebi.ac.uk/biostudies/studies/S-EPMC8505362biostudies-literatureUnknown12(9)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.Cell systemsDysregulation of the secretory pathway connects Alzheimer's disease genetics to aggregate formation.PMC8505362R01 AG015819R01 AG030146U01 AG046152R01 AG036836P30 AG010161U01 AG032984R35 GM119850R01 AG017917Kuo CCLewis NEBaghdassarian HMChiang AWTfalseDysregulation of the secretory pathway connects Alzheimer's disease genetics to aggregate formation.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.2021-01-01T00:00:00Z2021 Sep2024-11-15T20:15:19.702Z2024-11-15T20:15:19.702ZS-EPMC85053623417122810.1016/j.cels.2021.06.001