Abstract:

Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the soma where final degradation occurs. Here, we examined if axonal transport of autophagic vesicles is altered during aging. We employed two-photon microscopy for in vivo imaging in the optic nerve of young and aged rats. In old animals (> 18 months old), retrograde autophagic vesicle transport was significantly reduced with regard to motility and velocity. While activation of autophagy was decreased, expression of key proteins of the autophagy-lysosomal pathway including p62 and procathepsin D and the number of autophagolysosomes was increased. Maturation of autophagic vesicles was shifted to more distal regions of the axon and axonal lysosomal clearing was impaired. In a pull-down assay, the protein binding between dynein and dynactin was decreased by half, which could explain the retrograde axonal transport effects. Taken together, retrograde axonal autophagic vesicle transport in vivo is diminished during aging accompanied by decreased autophagy activation, alterations of the lysosomal pathway, and a reduced dynein-dynactin binding.

Key words: aging, autophagic vesicles, autophagy, autophagy-lysosomal pathway, axonal transport, dynein, optic nerve, p150Glued, retrograde transport, two-photon microscopy