In Alzheimer's disease, a therapy based on human recombinant Nerve Growth Factor (NGF) to prevent or slow the cognitive decline in AD patients has a strong scientific rationale, based on the pro-survival action of NGF on cholinergic neurons of the basal forebrain and on recent findings that show an anti-amyloidogenic action of NGF in cell and animal models. NGF delivery to the brain in a safe and long-term manner, limiting the adverse effects of NGF in activating nociceptive responses, has represented a significant challenge, due to the limited access of the protein to the brain and to peripheral nociceptive properties. This dual conflicting constraint has led to recent clinical studies based on the local administration of NGF directly into the brain parenchyma, through a gene-therapy approach requiring neurosurgery. Our laboratory proved that a non-invasive and highly effective delivery of NGF to the brain, through an intranasal route can rescue memory impairments and the AD-like neurodegeneration in the anti-NGF mouse model. The intranasal route has the property of facilitating the access of NGF to the CNS, bypassing the blood brain barrier, while minimizing the biodistribution of NGF to compartments where it can activate well known nociceptive effects. In addition, we further developed a hNGF double mutant (hNGFP61S/R100E) which displays reduced nociceptive responses, although maintaining its neurotrophic and anti-neurodegenerative properties in APPxPS1 mice. In this study we propose to perform (1) a pilot biodistribution and pharmacokinetic study to definitely answer to the questions related to the biodistribution and fate of hNGFP61S/R100E; (2) a dose-response study to establish the highest dose of hNGFP61S/R100E which does not trigger side-effects, i.e. pain.