Revealing the Molecular Mechanisms of Alzheimer’s DiseaseBased on Network Analysis

Abstract:

The complex pathology of Alzheimer’s disease (AD) emphasises the need for comprehensivemodelling of the disease, which may lead to the development of efficient treatment strategies.To address this challenge, we analysed transcriptome data of post-mortem human brain samples ofhealthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memoryand Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium.In this context, we conducted several bioinformatics and systems medicine analyses including theconstruction of AD-specific co-expression networks and genome-scale metabolic modelling of thebrain in AD patients to identify key genes, metabolites and pathways involved in the progression ofAD.We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in ADpatients. Moreover, we found alterations in energy metabolism, represented by reduced oxidativephosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA,(2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed thatneuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depletedin the AD brain, while neurotoxic metabolites (e.g., -alanine, bilirubin) were more abundant. Insummary, we systematically revealed the key genes and pathways related to the progression of AD,gained insight into the crucial mechanisms of AD and identified some possible targets that could beused in the treatment of AD.

Keywords: Alzheimer’s disease; gene co-expression network; genome-scale metabolic model; reportermetabolite analysis; energy metabolism