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Volume 16, Number 17, Issue of September 1, 1996 pp. 5437-5442
Copyright ©1996 Society for Neuroscience

Systemic Administration of a Nerve Growth Factor Conjugate Reverses Age-Related Cognitive Dysfunction and Prevents Cholinergic Neuron Atrophy

Received April 1, 1996; revised June 10, 1996; accepted June 12, 1996.

Cristina Bäckman³, Gregory M. Rose^{2, 3, 4}, Barry J. Hoffer^{2, 3}, Michael A. Henry¹, Raymond T. Bartus⁵, Phillip Friden⁵, and Ann-Charlotte Granholm^{1, 3}

Departments of ¹ Basic Science and ² Pharmacology, and ³ Neuroscience Training Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, ⁴ Medical Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, and ⁵ Alkermes Incorporated, Cambridge, Massachusetts 02139-4136

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration 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 experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.

Key words: septal nucleus; basal forebrain; neurotrophic factors; nerve growth factor; regeneration; plasticity; acetylcholine; Alzheimer's disease

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