Integrative analysis of OIP5-AS1/miR-129-5p/CREBBP axis as a potential therapeutic candidate in the pathogenesis of metal toxicity-induced Alzheimer's disease

Neurodegenerative disease, namely Alzheimer's disease (AD), is characterized by the accumulation of toxic β-amyloid aggregates and insoluble tau tangles. Mounting evidence demonstrated that heavy metals, such as copper, chromium, cobalt, and nickel, increase the β-amyloid and tau aggregation in the pathogenesis of AD by activating different signaling events. For instance, copper induces the formation of reactive oxygen species to cause mitochondrial dysfunction and DNA damage, whereas, chromium elevates neuroinflammatory response and neuronal apoptosis. Similarly, cobalt increases tau hyperphosphorylation and promotes tau aggregation, whereas, nickel elevates β-amyloid aggregation. Further, acetylation, a lysine-specific post-translational modification, has been linked to transcriptional activation, which regulates the transcription of genes associated with metal toxicity-induced AD. However, micro-RNAs (miRNAs) can reduce the activity of acetyltransferase, which decreases the transcriptional activation and thus inhibits the pathogenesis of AD. In contrast, long non-coding RNAs modulate the expression of specific miRNA and serve as a sponge to particular miRNA. In this study, we aim to identify the crucial proteins involved in metal toxicity-induced AD through network biology, followed by identifying regulatory transcription factors associated with crucial proteins. Further, we aim to determine the critical lysine residue and the role of CREBBP-induce acetylation on transcription factors. Lately, we have focused on identifying miRNAs associated with CREBBP and transcription factors simultaneously. Lastly, we aim to identify the potential long non-coding RNA, serving as a sponge to miRNAs. Our results demonstrated that the OIP5-AS1/miR-129-5p/CREBBP axis is a potential therapeutic target in metal toxicity-induced Alzheimer's disease pathogenesis.