Unlocking the role of miR-802 in molecular mechanisms underlying metabolic alterations in Down syndrome neuropathology

Down syndrome (DS) is characterised by a complex interplay of genetic and metabolic disturbances that culminate in early neurodegeneration and Alzheimer-like pathology. Among the molecular determinants contributing to this phenotype, microRNAs (miRNAs) encoded on chromosome 21 have emerged as pivotal post-transcriptional regulators. In particular, miR-802, consistently overexpressed in DS, has been implicated in metabolic dysregulation and insulin resistance (IR), two processes tightly linked to neuronal vulnerability. This study aimed to elucidate the molecular mechanisms through which miR-802 modulates insulin signalling and metabolic homeostasis in the DS brain. To this end, we combined analyses of human post-mortem cortical tissue with investigations in DS mouse models (Ts65Dn, Ts66Yah, Ts2Cje) and complementary in vitro systems, including HEK293 cells and primary astrocytes. Quantitative PCR and Western blot analyses revealed a significant upregulation of miR-802 in both human DS and DS-AD cortices and in trisomic mice, paralleled by a reduction of its direct target, glycogen synthase kinase-3β (GSK3β). Dual-luciferase reporter assays confirmed the specificity of miR-802–GSK3β interaction. Functional studies demonstrated that miR-802 overexpression impairs insulin-induced AKT activation, enhances inhibitory IRS1 phosphorylation, and exacerbates oxidative stress and mitochondrial dysfunction. Moreover, chronic insulin exposure increased miR-802 expression, indicating a reciprocal feedback loop between insulin resistance and miRNA dysregulation. In vivo, high-fat diet feeding potentiated miR-802 overexpression and further disrupted insulin signalling in trisomic mice, underscoring the synergistic effect of genetic and environmental factors. Collectively, these findings identify miR-802 as a key modulator of brain insulin signalling and mitochondrial homeostasis in DS, providing mechanistic insight into the early metabolic vulnerability that predisposes to neurodegeneration. Targeting miR-802-mediated pathways may therefore represent a promising strategy for mitigating cognitive decline and metabolic dysfunction in DS and related neurodegenerative conditions.