Dysregulation of the secretory pathway connects Alzheimer’s disease genetics to aggregate formation

• DOI: 10.1101/2020.08.10.243634
• Publication Date: 2020-08-11T00:30:26Z
• Authors: Chih-Chung Kuo; Austin WT Chiang; Hratch M. Baghdas...; Nathan E. Lewis
• Keywords: Secretory protein; Amyloid (mycology)

Abstract A hallmark of amyloid disorders, such as Alzheimer’s disease, is aggregation secreted proteins. However, it largely unclear how the hundreds secretory pathway proteins contribute to formation. We developed a systems biology framework that integrates expression data with protein-protein interaction networks successfully estimate tissue’s fitness for producing specific Using this framework, we analyzed various brain regions and cell types synthesizing disease-associated amyloid-precursor protein (APP). While none key amyloidogenic components were differentially expressed in AD brain, found deposition Aβ associated repressed proximal APP. Concurrently, detected systemic up-regulation β- γ-secretases brains. Our analyses suggest perturbations from 3 high confidence risk genes cascade through machinery support network APP into endocytosis pathway. Thus, present model where amyloidogenesis dysregulation dozens supporting APP, which could yield novel therapeutic targets treatment AD.