Micromanaging the brain Systematic assessment of a microRNA-based approach for Alzheimer's disease

Alzheimer’s disease (AD) is a progressive and multifactorial neurodegenerative disorder involving interconnected changes in, among others, neuronal function, neurogenesis, inflammation and general cellular homeostasis in the brain. Its complexity challenges conventional single-target therapeutic approaches and highlights the relevance of strategies capable of regulating multiple disease-related processes simultaneously. MicroRNAs (miRNAs) are small non-coding RNAs that regulate networks of target genes and thereby multiple biological pathways, making them promising candidates for such multi-target approaches.
This thesis systematically investigates the regulatory potential of miRNAs in AD-relevant processes, with a particular focus on miR-124. First, taking a broader perspective, we examine the roles of miRNAs in hippocampal plasticity, adult neurogenesis, neuroinflammation and cellular senescence. We further use single-cell transcriptomic analyses to characterize neural stem cell heterogeneity and age-associated changes that may contribute to altered brain plasticity during aging and AD. We then investigate neuron-targeted miR-124 supplementation in the dentate gyrus of the AppNL-G-F mouse model at different stages of AD-like pathology.
At an early, preclinical stage, miR-124 reduced intrinsic neuronal excitability, altered transcriptional programs related to synaptic organization and gliogenesis and was associated with increased numbers of immature neurons and microglia. At a more advanced disease stage, miR-124 reshaped inflammatory and synaptic gene expression, modified microglial and astrocytic responses and reduced regional amyloid-β plaque burden and soluble Aβ40 and Aβ42 levels.
Together, these findings demonstrate that miR-124 can modulate a series of molecular, cellular and niche-level neuronal and microglial processes in a disease-stage-dependent manner, highlighting both the potential and complexity of miRNA-based multi-target strategies for AD.