Portal de Periódicos da CAPES

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

2007; National Academy of Sciences; Volume: 104; Issue: 7 Linguagem: Inglês

10.1073/pnas.0609377104

1091-6490

William V. Nikolic, Yun Bai, Demian Obregon, Huayan Hou, T. Mori, Jin Zeng, Jared Ehrhart, R. Douglas Shytle, Brian Giunta, Dave Morgan, Terrence Town, Jun Tan,

Prion Diseases and Protein Misfolding

Alzheimer's disease (AD) immunotherapy accomplished by vaccination with β-amyloid (Aβ) peptide has proved efficacious in AD mouse models. However, “active” Aβ vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Aβ 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 Aβ 1–42 plus the adjuvant cholera toxin (CT) results in high-titer Aβ antibodies (mainly of the Ig G1 class) and Aβ 1–42 -specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Aβ 1–42 immunogen, suggesting that these unique innate immune cells participate in Aβ 1–42 antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Aβ 1–42 peptide plus CT. Similar to WT mice, PSAPP mice showed high Aβ antibody titers. Most importantly, t.c. immunization with Aβ 1–42 plus CT resulted in significant decreases in cerebral Aβ 1–40,42 levels coincident with increased circulating levels of Aβ 1–40,42 , suggesting brain-to-blood efflux of Aβ. 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.