Integrated multi-omics analysis of Alzheimer's disease shows molecular signatures associated with disease progression and potential therapeutic targets.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of amyloid plaques implicated in neuronal death. Genetics, age, and sex are the risk factors attributed to AD. Though omics studies have helped to identify pathways associated with AD, an integrated systems analysis with the available data could help to understand mechanisms, potential biomarkers, and therapeutic targets. Analysis of transcriptomic data sets from the GEO database, and proteomic and metabolomic data sets from literature was performed to identify deregulated pathways and commonality analysis identified overlapping pathways among the data sets. The deregulated pathways included those of neurotransmitter synapses, oxidative stress, inflammation, vitamins, complement, and coagulation pathways. Cell type analysis of GEO data sets showed microglia, endothelial, myeloid, and lymphoid cells are affected. Microglia are associated with inflammation and pruning of synapses with implications for memory and cognition. Analysis of the protein-cofactor network of B2, B6, and pantothenate shows metabolic pathways modulated by these vitamins which overlap with the deregulated pathways from the multi-omics analysis. Overall, the integrated analysis identified the molecular signature associated with AD. Treatment with anti-oxidants, B2, B6, and pantothenate in genetically susceptible individuals in the pre-symptomatic stage might help in better management of the disease.

Integrated multi-omic data analysis and validation with yeast model show oxidative phosphorylation modulates protein aggregation in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis is a progressive, incurable amyloid aggregating neurodegenerative disease involving the motor neurons. Identifying potential biomarkers and therapeutic targets can assist in the better management of the disease. We used an integrative approach encompassing analysis of transcriptomic datasets of human and mice from the GEO database. Our analysis of ALS patient datasets showed deregulation in Non-alcoholic fatty acid liver disease and oxidative phosphorylation. Transgenic mice datasets of SOD1, FUS and TDP-43 showed deregulation in oxidative phosphorylation and ribosome-associated pathways. Commonality analysis between the human and mice datasets showed oxidative phosphorylation as a major deregulated pathway. Further, protein-protein and protein-drug interaction network analysis of mitochondrial electron transport chain showed enrichment of proteins and inhibitors of mitochondrial Complex III and IV. The results were further validated using the yeast model system. Inhibitor studies using metformin (Complex-I inhibitor) and malonate (Complex-II inhibitor) did not show any effect in mitigating the amyloids, while antimycin (Complex-III inhibitor) and azide (Complex-IV inhibitor) reduced amyloidogenesis. Knock-out of QCR8 (Complex-III) or COX8 (Complex-IV) cleared the amyloids. Taken together, our results show a critical role for mitochondrial oxidative phosphorylation in amyloidogenesis and as a potential therapeutic target in ALS.Communicated by Ramaswamy H. Sarma.