title: Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice.
abstract: BACKGROUND
  It is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response.
  
  
  RESULTS
  We have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A) was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP), and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden) in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens.
  
  
  CONCLUSIONS
  These results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
authors.forename: Suhail
authors.initials: S
authors.lastname: Rasool
authors.forename: Ricardo
authors.initials: R
authors.lastname: Albay
authors.forename: Hilda
authors.initials: H
authors.lastname: Martinez-Coria
authors.forename: Leonid
authors.initials: L
authors.lastname: Breydo
authors.forename: Jessica
authors.initials: J
authors.lastname: Wu
authors.forename: Saskia
authors.initials: S
authors.lastname: Milton
authors.forename: Sunit
authors.initials: S
authors.lastname: Misra
authors.forename: Andy
authors.initials: A
authors.lastname: Tran
authors.forename: Anna
authors.initials: A
authors.lastname: Pensalfini
authors.forename: Frank
authors.initials: F
authors.lastname: Laferla
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000941:Antigens / Q000276:immunology; D040761:Biomimetic Materials; D003071:Cognition / Q000502:physiology*; D006470:Hemorrhage / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology*; D055503:Protein Multimerization; D014611:Vaccination
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D000941:Antigens