Abstract: Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles – microvesicles carrying biomolecular cargos – that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer’s disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell–derived small extracellular vesicles protection of synapses against Alzheimer’s disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescence-labeled small extracellular vesicles injected into wild-type mice brains were taken up by microglia, with only neural stem cell–derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell–derived small extracellular vesicle administration. Single-nuclei RNA-sequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell–derived small extracellular vesicle-induced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell–derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell–derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell–derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell–derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell–derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer’s disease.

Key words: Alzheimer’s diseasel hippocampusl immune responsel lysosomesl microglial neural stem cellsl neuroinflammationl single-nuclei RNA sequencingl small extracellular vesiclesl Tau oligomers