title: Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage.
abstract: Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (Abeta) peptide has proved efficacious in AD mouse models. However, "active" Abeta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Abeta 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 Abeta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Abeta(1-42) immunogen, suggesting that these unique innate immune cells participate in Abeta(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 Abeta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high Abeta antibody titers. Most importantly, t.c. immunization with Abeta(1-42) plus CT resulted in significant decreases in cerebral Abeta(1-40,42) levels coincident with increased circulating levels of Abeta(1-40,42), suggesting brain-to-blood efflux of Abeta. 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.
authors.affiliation: Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Nikolic
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Demian
authors.initials: D
authors.lastname: Obregon
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000276:immunology / Q000627:therapeutic use; D000686:Amyloidosis; D000818:Animals; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000209:etiology; D002634:Chemotaxis, Leukocyte; D007801:Langerhans Cells / Q000276:immunology; D008590:Meningoencephalitis / Q000209:etiology; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes; D016896:Treatment Outcome; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)