Engrailed, a target of the miR-92 family, attenuates Tau accumulation and associated memory deficits in Drosophila.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated Tau protein. While microRNAs (miRNAs) have emerged as critical regulators of gene expression and potential biomarkers for AD, their role in Tau pathology remains incompletely understood. In this study, we investigated the role of the miR-92 family and its downstream targets in modulating Tau-induced neurodegeneration using the Drosophila model. Overexpression of miR-311, miR-312, and miR-313, members of the miR-92 family, exacerbated Tau-induced phenotypes. We identified deltex (dx) and engrailed (en) as miR-92 target genes with genetic screening with in silico target prediction. Overexpression of en or EN2, a human ortholog of en, reduced Tau protein levels in Drosophila and human neuroblastoma cells, respectively. Furthermore, overexpression of en attenuates Tau-associated memory deficits in Drosophila. These findings suggest that the engrailed gene is an evolutionarily conserved regulator of Tauopathy and highlight the utility of the Drosophila AD model for identifying genetic modulators with therapeutic potential in AD.