miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer's disease

MicroRNA-124 (miR-124) has been proposed as therapeutic candidate for Alzheimer's disease (AD), given its regulation of gene networks governing synaptic function, neurogenesis and inflammation. However, its functional role during early disease stages, and the cellular context-dependence of its effects, remain unclear. Here, we investigated the effects of targeted neuronal miR-124 delivery to the hippocampal dentate gyrus (DG) of AppNL-G-F mice. At an earlier 'presymptomatic' stage, miR-124 reduced intrinsic excitability of mature granule neurons and induced subtle changes in dendritic architecture. Integrative transcriptomic analyses revealed that predicted miR-124 targets were enriched among downregulated genes involved in synapse organization and cell junction assembly. At the same time, miR-124 increased the number of immature neurons and microglia, indicating structural and functional remodeling of the DG. At a later 'symptomatic' disease stage, where AD pathology is established, neuronal miR-124 supplementation reduced DG Aβ₄₀ and Aβ₄₂ levels and decreased local amyloid plaque burden, while also altering the plaque-associated microglial response. Together, these findings identify neuronal miR-124 as a context- and disease-stage-dependent regulator of the DG microenvironment and demonstrate effects extending from neuronal function to other cellular populations and local AD-associated pathology.