Age-Induced Nitrative Stress Decreases Retrograde Transport of ProNGF via TrkA and Increases ProNGF Retrograde Transport and Neurodegeneration via p75NTR

In this study, fluorescence microscopy was used to analyze axonal transport of quantum dot labelled proNGF in rat BFCNs in vitro. Receptor specific effects were studied with proNGF mutants that selectively bind to either TrkA (proNGF-KKE) or p75NTR (proNGF-Δ9-13). Signalling factor activity was quantified via immunostaining. Young BFCNs transported proNGF-KKE but not proNGF-Δ9-13, and proNGF transport was not different in p75NTR knockout BFCNs compared to wildtype BFCNs. These results indicate that young BFCNs transport proNGF via TrkA. In vitro aging increased transport of proNGF-Δ9-13 but decreased transport of proNGF-KKE. Treatment with the nitric oxide synthase inhibitor L-NAME reduced retrograde transport of proNGF-Δ9-13 in aged BFCNs while increasing retrograde transport of proNGF-KKE but did not affect TrkA and p75NTR levels. ProNGF-Δ9-13 induced greater pro-apoptotic signalling and neurodegeneration and less pro-survival signalling relative to proNGF-KKE. Together, these results indicate that age-induced nitrative stress decreases proNGF transport via TrkA while increasing proNGF transport via p75NTR. These transport deficits are associated with decreased survival signalling, increased apoptotic signalling, and neurodegeneration.