SYSTEMIC ADMINISTRATION OF A NERVE GROWTH-FACTOR CONJUGATE REVERSES AGE-RELATED COGNITIVE DYSFUNCTION AND PREVENTS CHOLINERGIC NEURON ATROPHY

Intraventricular administration of nerve growth factor (NGF) in rats h as been shown to reduce age-related atrophy of central cholinergic neu rons and the accompanying memory impairment. Intraventricular administ ration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26 ), to transport biologically active NGF across the BBB. In our experim ent, aged (24 months old) Fischer 344 rats received intravenous inject ions of the OX-26-NGF conjugate or a control solution (a mixture of un conjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF inje ctions resulted in a significant improvement in spatial learning in pr eviously impaired rats but disrupted the learning ability of previousl y unimpaired rats, Neuroanatomical analyses showed that OX-26-NGF conj ugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatia l learning. These results indicate the potential use of the transferri n receptor antibody delivery system for treatment of CNS disorders wit h neurotrophic proteins.