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

• William V. Nikolic

  *Department of Psychiatry and Behavioral Medicine,

• Yun Bai

  *Department of Psychiatry and Behavioral Medicine,

• Demian Obregon

  *Department of Psychiatry and Behavioral Medicine,

• Huayan Hou

  *Department of Psychiatry and Behavioral Medicine,

• Takashi Mori

  *Department of Psychiatry and Behavioral Medicine,

• Jin Zeng

  *Department of Psychiatry and Behavioral Medicine,

• Jared Ehrhart

  *Department of Psychiatry and Behavioral Medicine,

• R. Douglas Shytle

  *Department of Psychiatry and Behavioral Medicine,

• Brian Giunta

  *Department of Psychiatry and Behavioral Medicine,

• Dave Morgan

  Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613;

• Terrence Town

  Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8011; and

• Jun Tan

  *Department of Psychiatry and Behavioral Medicine,

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 104 (7), 2507-2512, 2007-02-13

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361981469433033728
• NII論文ID: 80017907807
• DOI: 10.1073/pnas.0609377104
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0609377104
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