145 | Synergistic effects of APP and Tau on neuronal miRNA regulation

Laura M. De Plano¹, Alessandra Saitta¹, Antonella Caccamo¹, Emanuele L. Sciuto¹, Sabrina Conoci², Salvatore Oddo¹ | ¹Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy; ²Dipartimento di Chimica "Giacomo Ciamician", University of Bologna, Italy.

MicroRNA (miRNA) dysregulation is implicated in Alzheimer’s disease pathogenesis, but the impact of Tau pathology on miRNA responses to amyloid precursor protein (APP) alterations remains poorly understood. In this study, we examined the expression of a selected panel of miRNAs (miR-125b, miR-21, miR-155, miR-132, and miR-181a) in SH-SY5Y neuroblastoma cells and in SH-SY5Y cells carrying the Tau P306L mutation. Cells were transfected with plasmids encoding either APP695 or the Swedish mutant APP (APP-Swe), and miRNA expression was quantified by qPCR with global mean normalization. Two-way ANOVA was used to evaluate the effects of APP condition, Tau genotype, and their interaction. Results revealed distinct miRNA expression profiles driven primarily by Tau status and APP expression. Specifically, miR-125b and miR-155 were significantly influenced by both APP condition and cell type, indicating independent and additive effects. miR-21 expression was predominantly regulated by APP, with no significant contribution from Tau genotype or interaction. In contrast, miR-132 and miR-181a showed significant APP×Tau interactions, indicating that mutant Tau modifies the cellular response to APP in regulating these miRNAs. These findings suggest that miRNA dysregulation in this neuronal model is not solely driven by amyloidogenic stress, but results from differential and sometimes interactive effects of APP and Tau. In parallel, the expression of selected mitochondrial respiratory chain genes showed a coordinated remodeling of the electron transport chain, characterized by APP-associated down-regulation of the Complex I subunit and a Tau-dependent modulation of Complex IV, consistent with a shift from compensatory to dysfunctional mitochondrial responses in the presence of Tau pathology. Overall, our data support a model in which Tau pathology is a key determinant of APP-induced miRNA regulation, highlighting early post-transcriptional mechanisms that may contribute to neurodegenerative progression.

This work was funded by the European Union (NextGeneration EU) through the MUR-PNRR project SAMOTHRACE. CUP J43C22000310006 - codice identificativo ECS00000022.