Stable Vesicle-Associated BDNF from Embryonic and Young Cortical Extracellular Vesicles

In this work we show that small extracellular vesicles (sEVs) from embryonic mouse cortex or from cultured embryonic cortical neurons contain high levels of BDNF and sustain TrkB-dependent neuroprotective signaling. By contrast, sEVs from aged cortex are depleted of BDNF, and cells lacking active TrkB fail to mount a protective response when exposed to the same sEVs. Biochemical fractionation and trypsin sensitivity assay indicate that BDNF is a constitutive EV component and is exposed on or tightly associated with the vesicle surface, an arrangement that likely increases local ligand density. In a stability assay, EV-associated BDNF retained activity longer than soluble BDNF. Together, our findings suggest that many developmental effects of BDNF may be mediated by EVs, that impaired stress responses in the aged brain could reflect reduced formation of BDNF-containing EVs, and that embryonic sEVs may provide a more efficient vehicle for BDNF delivery than current therapeutic approaches.