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An aqueous orally active vaccine targeted against a RAGE/AB complex as a novel therapeutic for Alzheimer's disease.

Authors: Webster, SJ  Mruthinti, S  Hill, WD  Buccafusco, JJ  Terry AV, JR 
Citation: Webster SJ, etal., Neuromolecular Med. 2012 Jun;14(2):119-30. doi: 10.1007/s12017-012-8176-z. Epub 2012 Mar 14.
Pubmed: (View Article at PubMed) PMID:22415896
DOI: Full-text: DOI:10.1007/s12017-012-8176-z

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that gradually destroys a person's memory. Substantial evidence suggests that amyloid beta (Abeta) 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 Abeta from the periphery into the brain, mediates the Abeta-induced neurotoxicity, and enhances the release of pro-inflammatory cytokines increasing the inflammatory response. In addition, soluble forms of RAGE (sRAGE) and Abeta bind together in the periphery forming high molecular weight complexes that are more highly immunogenic and less neurotoxic than Abeta1-42 alone. We show here that there are elevated anti-RAGE and anti-Abeta 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/Abeta complex induces a greater immunogenic response (increased anti-Abeta1-42 and anti-RAGE antibody titers) in both human peripheral blood mononuclear cells (PBMCs) and immunized Balb-C mice than does either Abeta1-42 or RAGE alone. Further, pretreatment with endogenous anti-RAGE antibodies isolated from our transgenic APPSWE-PS1 mice can prevent Abeta1-42-induced neurotoxicity in cultured primary rat cortical neurons. Finally, we examine the effectiveness of an orally administered vaccine of either RAGE/Abeta complex or Abeta1-42 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 Abeta1-42 will provide a more effective treatment for AD than vaccination with Abeta1-42 alone.

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CRRD Object Information
CRRD ID: 7245561
Created: 2013-06-11
Species: All species
Last Modified: 2013-06-11
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.