Effects of intranasally-delivered pro-nerve growth factors on the septohippocampal system in healthy and diabetic rats

Pro-nerve growth factor (proNGF) is the predominant form of NGF in the brain and its levels increase in neurodegenerative diseases. The balance between NGF receptors may explain the contradictory biological activities of proNGF. However, the specific role of the two main proNGF variants is mostly unexplored. proNGF-A is prevalently expressed in healthy brain, while proNGF-B content increases in the neuro-degenerating brain. Recently we have investigated in vitro the biological action of native mouse proNGF variants. To gain further insights into the specific functions of the two proNGFs, here we intranasally delivered mouse-derived proNGF-A and proNGF-B to the brain parenchyma of healthy and diabetic rats, the latter characterized by dysfunction in spatial learning and memory, in the septo-hippocampal circuitry and by relative increase in proNGF-B hippocampal levels. Exogenous proNGF-B induces depression of hippocampal DG-LTP and impairment of hippocampal neurogenesis in healthy animals, with concomitant decrease in basal forebrain cholinergic neurons and cholinergic fibers projecting to the hippocampus. proNGF-A, while ineffective in healthy animals, rescues the diabetes- induced impairment in DG-LTP and hippocampal neurogenesis, promoting the concomitant recovery of the basal forebrain cholinergic phenotype. Our experimental evidences suggest that the balance between different proNGFs may influence the development and progression of neurodegenerative diseases.