Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (A beta) peptide has proved efficacious in AD mouse models. However, "active" A beta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) A beta vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated A beta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer A beta antibodies (mainly of the Ig G1 class) and A beta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the A beta(1-42) immunogen, suggesting that these unique innate immune cells participate in A beta(1-42) antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APP(sw), PSEN1dE9) mice were immunized with aggregated A beta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high A beta antibody titers. Most importantly, t.c. immunization with A beta(1-42) plus CT resulted in significant decreases in cerebral A beta(1-40),42 levels coincident with increased circulating levels of A beta 1-40,42, suggesting brain-to-blood efflux of A beta. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.