title: Preventive immunization of aged and juvenile non-human primates to β-amyloid.
abstract: BACKGROUND
  Immunization against beta-amyloid (Aβ) is a promising approach for the treatment of Alzheimer's disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu.
  
  
  METHODS
  Ten non-human primates (NHP) of advanced age (18-26 years) and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [(11)C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals.
  
  
  RESULTS
  All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [(11)C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P < 0.01). No differences were seen in microglial density or expression of classical and alternative microglial activation markers between immunized and control animals.
  
  
  CONCLUSIONS
  Our results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system activation or other serious side-effects in both aged and juvenile NHP cohorts. A significant shift in the composition of soluble oligomers towards smaller species might facilitate removal of toxic Aβ species from the brain.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA. koflerjk@upmc.edu
authors.forename: Julia
authors.initials: J
authors.lastname: Kofler
authors.forename: Brian
authors.initials: B
authors.lastname: Lopresti
authors.forename: Chris
authors.initials: C
authors.lastname: Janssen
authors.forename: Anita M
authors.initials: AM
authors.lastname: Trichel
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Olivera J
authors.initials: OJ
authors.lastname: Finn
authors.forename: Russell D
authors.initials: RD
authors.lastname: Salter
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Murdoch
authors.forename: Chester A
authors.initials: CA
authors.lastname: Mathis
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Wiley
mesh_terms: D000367:Age Factors; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D023582:Alzheimer Vaccines / Q000008:administration & dosage* / Q000276:immunology* / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007114:Immunization / Q000379:methods*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008254:Macaca nemestrina; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)