Overexpressed MicroRNA-455-3p enhances cognitive function in late-onset Alzheimer's disease

MicroRNAs (miRNAs) are emerging as key regulators of neurodegenerative diseases, including Alzheimer's disease (AD). miR-455-3p has been implicated in neuronal function, yet its role in cognition, motor function, and behavioral responses, in relation to AD remains unexplored. This study investigates the effects of miR-455-3p overexpression and knockout in late-onset humanized Amyloid beta (hAbKI) mouse model. We crossed miR-455-3p transgenic (TG) and knockout (KO) mice with hAbKI mice, generated double mutant mice (miR-455-3p Tg X hAbKI and miR-455-3p KO X hAbKI) and assessed cognitive behavior. To evaluate behavioral phenotype, we used cognitive and motor tests in six experimental groups-wild-type (WT), miR-455-3p KO, miR-455-3p TG, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI-to the Morris Water Maze (MWM), Y-maze, open field, and rotarod tests. miR-455-3p overexpression in TG mice significantly enhanced locomotor activity (open field test), working memory (Y-maze), hippocampal spatial learning & memory (MWM), and motor coordination (rotarod test). In contrast, miR-455-3p KO and KO X hAbKI mice exhibited impaired cognitive functionand reduced motor performance. In addition, miR-455-3p KO and KO X hAbKI mice showed increased anxiety-like behavior in the light-dark (LD) test. Notably, the hAbKI X miR-455-3p KO group displayed the most severe deficits, suggesting that the loss of miR-455-3p exacerbates AD-related impairments. Statistical analyses confirmed significant group differences (p < 0.05), with post-hoc tests demonstrating superior performance in the TG group compared to KO and hAbKI X miR-455-3p KO mice. These findings suggest that miR-455-3p plays a significant role in regulating cognitive and motor functions, with its overexpression conferring neuroprotective benefits. Targeting miR-455-3p may provide novel strategies for improving cognitive and motor outcomes in AD and related conditions.