CO-INFUSION WITH A TRKB-FC RECEPTOR BODY CARRIER ENHANCES BDNF DISTRIBUTION IN THE ADULT-RAT BRAIN

Fusion proteins comprising the Fc domain of human IgG and extracellula r domains of receptor tyrosine kinases can neutralize the activity of their cognate Ligands when administered in molar excess. We have gener ated a fusion protein using the ectodomain of TrkB (TrkB-Fc). Although the ability of TrkB-Fc to neutralize the activity of brain-derived ne urotrophic factor (BDNF) in vitro has been demonstrated, there have be en no conclusive demonstrations of its ability to neutralize the activ ity of BDNF in vivo. We coinfused TrkB-Fc with BDNF into the cortex an d hippocampus of adult rats to determine whether TrkB-Fc would interfe re with the ability of BDNF to upregulate neuropeptide Y (NPY). We rep ort here that rather than neutralizing the activity of exogenous BDNF, coinfusion with the TrkB-Fc fusion protein greatly increased the volu me of tissue in which neuropeptide Y immunostaining was upregulated. I n addition, TrkB-Fc greatly enhanced BDNF's distribution through adult brain parenchyma. TrkB-Fc also markedly increased the otherwise limit ed diffusion of BDNF into brain parenchyma following intraventricular infusion. These results show that rather than neutralizing or sequeste ring BDNF, the TrkB-Fc, at close to molar equivalence to BDNF, can fun ction as a carrier for BDNF and thus enhance the delivery or penetrati on of this polypeptide into the brain. (C) 1998 Academic Press.