The common genes involved in the pathogenesis of Alzheimer's disease and type 2 diabetes and their implication for drug repositioning.

ABSTRACT

BACKGROUND: The prevalences of Alzheimer's disease (AD) and type 2 diabetes (T2D) continuously increase with the aging of world population. Clinical and epidemiological studies indicate that T2D is an important risk factor for AD. However, the mechanisms underlying the linkage of the two disorders are still not fully elucidated. The aim of this study is to explore the molecular mechanisms of their comorbidity and potential drug targets for AD treatment. METHODS: We first compiled comprehensive lists of genes associated with AD and T2D, respectively. Then, we investigated the signatures of the shared genes and screened for interactions between the hub genes. Subsequently, we used Autodock Vina to perform molecular docking to predict new drug candidates. Lastly, structure and dynamics of docking results were examined by molecular dynamics simulation to verify drug reliability. RESULTS: We obtained 917 AD-associated genes, 631 T2D-associated genes and 175 shared genes between the two disorders for subsequent analyses. Functional analysis revealed that metabolic process, lipid and atherosclerosis, AMPK signaling pathway, insulin resistance, chemokines and cytokines were enriched in the shared genes. In addition, 50 central hub genes were identified, including IL6, TNF, INS, IL1B, AKT1, VEGFA, IL10, TP53, PTGS2, TLR4, and others. Finally, we predicted new drug candidates (verdoheme and stannsoporfin) that could be potentially used for AD treatment. CONCLUSIONS: Our study confirmed that there are important shared genes and pathways between AD and T2D, which may provide clues to reveal the molecular mechanism underlying the pathophysiology of the two diseases and help us to discover novel drug candidates for the treatment of AD. The results may also provide clues into identification of new targets and strategies for prevention and therapy of T2D that predisposes to AD.