Sporadic Alzheimer’s Disease- and Neurotoxicity-Related microRNAs Affecting Key Events of Tau-Driven Adverse Outcome Pathway Toward Memory Loss

Abstract

Background: A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer’s disease (sAD). Objective: Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. Methods: Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to create miR-target interaction networks. Results: The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. Conclusion: Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms.