Therapeutic effects of anti-amyloid β antibody after intravenous injection and efficient nose-to-brain delivery in Alzheimer's disease mouse model.

Antibody drugs that target amyloid β (Aβ) are considered possible treatments for Alzheimer's disease; however, most have been dropped from clinical trials. We hypothesized that administration route for antiAβ antibody (AntiAβ) might affect its therapeutic potential and thus compared delivery of antibodies to the brain and their effect on cognitive dysfunction and amyloid disposition via intravenous (i.v.) and intranasal routes with and without the cell-penetrating peptide, L-penetratin. We demonstrated that intranasal administration with L-penetratin more efficiently delivered human immunoglobulin G (IgG), a model molecule for AntiAβ, to the brain compared with i.v. injection. We found that multiple intranasal treatments with Alexa 594-labeled AntiAβ (A594-AntiAβ) with L-penetratin significantly improved learning by mice with aged amyloid precursor protein (APP) knock-in (App KI mice). Further, intranasal administration of A594-AntiAβ increased the amount of soluble Aβ (1-42) in the brain, suggesting suppression of Aβ aggregation in insoluble form and involvement of activated microglia in Aβ clearance. Thus, administration route may be critical for efficient delivery of AntiAβ to the brain, and the nose-to-brain delivery with L-penetratin can maximize its therapeutic efficacy.