title: An aqueous orally active vaccine targeted against a RAGE/AB complex as a novel therapeutic for Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that gradually destroys a person's memory. Substantial evidence suggests that amyloid beta (Aβ) and the receptor for advanced glycation endproducts (RAGE) play an important and often deleterious role in the pathogenesis of AD. RAGE facilitates the translocation of Aβ from the periphery into the brain, mediates the Aβ-induced neurotoxicity, and enhances the release of pro-inflammatory cytokines increasing the inflammatory response. In addition, soluble forms of RAGE (sRAGE) and Aβ bind together in the periphery forming high molecular weight complexes that are more highly immunogenic and less neurotoxic than Aβ1-42 alone. We show here that there are elevated anti-RAGE and anti-Aβ titers (in a near 1:1 relationship) in samples analyzed from human AD patients, aged non-human primates, and AD transgenic mice (APPSWE-PS1). We show that an in vitro prepared RAGE/Aβ complex induces a greater immunogenic response (increased anti-Aβ1-42 and anti-RAGE antibody titers) in both human peripheral blood mononuclear cells (PBMCs) and immunized Balb-C mice than does either Aβ1-42 or RAGE alone. Further, pretreatment with endogenous anti-RAGE antibodies isolated from our transgenic APPSWE-PS1 mice can prevent Aβ1-42-induced neurotoxicity in cultured primary rat cortical neurons. Finally, we examine the effectiveness of an orally administered vaccine of either RAGE/Aβ complex or Aβ1-42 alone in improving cognitive function in our AD transgenic mice. Our results to date support the hypothesis that a protein complex vaccine that targets both RAGE and Aβ1-42 will provide a more effective treatment for AD than vaccination with Aβ1-42 alone.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Webster
authors.forename: Shyamala
authors.initials: S
authors.lastname: Mruthinti
authors.forename: William David
authors.initials: WD
authors.lastname: Hill
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000276:immunology / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000276:immunology*
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42)