miR-484 in Hippocampal Astrocytes of Aged and Young Rats Targets CSF-1 to Regulate Neural Progenitor/Stem Cell Proliferation and Differentiation Into Neurons.

Aim: Aging-related cognitive decline is closely linked to the reduced function of neural progenitor/stem cells (NPSCs), which can be influenced by the neural microenvironment, particularly astrocytes. The aim of this study was to explore how astrocytes affect NPSCs and cognitive function during aging.

Methods: HO-treated astrocytes were used to mimic the aging phenotype of astrocytes. Proteomic analysis identified altered protein expression, revealing high levels of colony-stimulating factor-1 (CSF-1) in the supernatant of HO-treated astrocytes. Primary NPSCs were isolated and cultured in vitro, then stimulated with varying concentrations of recombinant CSF-1 protein to assess its effects on NPSC proliferation, differentiation, and apoptosis. Transcriptome sequencing identified miR-484 related to CSF-1 in HO-treated astrocytes, and a dual-luciferase assay verified the interaction between miR-484 and CSF-1. The impact of miR-484 overexpression on NPSC function and cognitive restoration was evaluated both in vitro and in vivo (in 20-month-old rats).

Results: High concentration of CSF-1 inhibited the NPSC proliferation and differentiation into neurons while inducing apoptosis. Overexpression of miR-484 downregulated CSF-1 expression by binding to its 3' untranslated region, thereby promoting the NPSC proliferation and differentiation into neurons. In 20-month-old rats, miR-484 overexpression improved spatial learning and memory in the Morris water maze, increased NPSC proliferation, and reduced apoptosis.

Conclusion: Our findings reveal that miR-484 regulates CSF-1 to influence NPSC proliferation, differentiation into neurons, and apoptosis, consequently improving cognitive function in 20-month-old rats. This study provides a foundation for developing therapeutic strategies targeting age-related hippocampal cognitive impairments.