Nerve Growth Factor (NGF) has a great potential for the treatment of Alzheimer's disease. However, the therapeutic administration of NGF represents a significant challenge, due to the difficulty to deliver relevant doses to the brain, in a safe and non-invasive way.

We previously demonstrated the efficacy of a non invasive delivery of NGF to the brain in animal models, by an intranasal route. Recently, topical eye application of NGF was proposed, as an option for the delivery of NGF to the brain. Here, we compare the efficacy of the two delivery routes of hNGF-61, a recombinant traceable form of human NGF, in the mouse neurodegeneration model AD11. The intranasal administration appeared to be significantly more effective than the ocular one, in rescuing the neurodegenerative phenotypic hallmarks in AD11 mice. The ocular administration of hNGF-61 showed a more limited efficacy, even at higher doses. In addition, we used the rescue of the shrinkage of superior cervical ganglia as a parameter to indicate leakage of hNGF-61 in the peripheral blood circulation. We show that only through the intranasal route there are no effects on the peripheral target, suggesting that the ocular administration may be not sufficient to prevent the onset of peripheral side effects, such as pain. Thus, NGF nasal drops represent a viable and effective option to successfully deliver therapeutic NGF to the brain in a non-invasive manner.