Intranasal administration is emerging as a reliable and non-invasive method to bypass the blood-brain barrier and deliver drugs to the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. However, intranasal administration could also be used to create animal models of brain disease. Beta-amyloid peptide (Aβ) accumulation is a key feature of Alzheimer's disease (AD), and the most common models of AD are transgenic mice expressing mutant human genes linked to familial AD. An alternative model of amyloidosis utilizes intracerebroventricular infusion of thiorphan or phosphoramidon to block the activity of key Aβ degrading enzymes (NEP, NEP2) resulting in accumulation of Aβ. Here, we demonstrate that intranasal administration of phosphoramidon produces significantly elevated cerebral Aβ levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also showed increased levels of Aβ(40). These data show that intranasal delivery of drugs can be used to model AD and suggest that other phosphoramidon-sensitive peptidases are degrading Aβ in NEP/NEP2-deficient mice.