Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo

Abstract

Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4), together with nerve growth factor and brain-derived neurotrophic factor, are members of the neurotrophin family of proteins, which supports the survival of vertebrate neurons. However, no function in vivo has been described for NT-4 and limited information is available on the role of the other neurotrophins in the central nervous system in vivo. Nerve growth factor prevents the degeneration of lesioned septal cholinergic neurons in the adult brain, whereas brain-derived neurotrophic factor prevents the death of developing motor neurons and a subpopulation of adult septal cholinergic neurons. Finally, NT-3 partially prevents the death of facial motor neurons in newborn rats. To assess the role of NT-3 and NT-4 in the adult brain in vivo, we implanted genetically modified fibroblasts that constitutively express high levels of NT-3 or NT-4. The results show that NT-3, but no other neurotrophin, prevents the degeneration of noradrenergic neurons of the locus coeruleus in a 6-hydroxydopamine lesion model that resembles the pattern of cell loss found in Alzheimer's disease. These results imply that NT-3 may have therapeutic potential for preventing the death of noradrenergic neurons in the locus coeruleus.