Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model

Alzheimer's disease (AD) is pathologically characterized by extracellular beta-amyloid (A beta) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these A beta plaques and the A beta-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small A beta depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the A beta degrading enzyme neprilysin delivered to the mouse brain can clear A beta plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect.

Automated summary

The study aimed to investigate if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model, and found that collagen and platelets are potential vehicles for delivering neprilysin into the brain.