title: Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis.
abstract: BACKGROUND
  Abnormal tau hyperphosphorylation and its accumulation into intra-neuronal neurofibrillary tangles are linked to neurodegeneration in Alzheimer's disease and similar tauopathies. One strategy to reduce accumulation is through immunization, but the most immunogenic tau epitopes have so far remained unknown. To fill this gap, we immunized mice with recombinant tau to build a map of the most immunogenic tau epitopes.
  
  
  METHODS
  Non-transgenic and rTg4510 tau transgenic mice aged 5 months were immunized with either human wild-type tau (Wt, 4R0N) or P301L tau (4R0N). Each protein was formulated in Quil A adjuvant. Sera and splenocytes of vaccinated mice were collected to assess the humoral and cellular immune responses to tau. We employed a peptide array assay to identify the most effective epitopes. Brain histology was utilized to measure the effects of vaccination on tau pathology and inflammation.
  
  
  RESULTS
  Humoral immune responses following immunization demonstrated robust antibody titers (up to 1:80,000 endpoint titers) to each tau species in both mice models. The number of IFN-γ producing T cells and their proliferation were also increased in splenocytes from immunized mice, indicating an increased cellular immune response, and tau levels and neuroinflammation were both reduced. We identified five immunogenic motifs within either the N-terminal (9-15 and 21-27 amino acids), proline rich (168-174 and 220-228 amino acids), or the C-terminal regions (427-438 amino acids) of the wild-type and P301L tau protein sequence.
  
  
  CONCLUSIONS
  Our study identifies five previously unknown immunogenic motifs of wild-type and mutated (P301L) tau protein. Immunization with both proteins resulted in reduced tau pathology and neuroinflammation in a tau transgenic model, supporting the efficacy of tau immunotherapy in tauopathy.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B Downs Blvd, Tampa 33612, FL, USA. mselenic@health.usf.edu.
authors.forename: Maj-Linda B
authors.initials: ML
authors.lastname: Selenica
authors.forename: Hayk
authors.initials: H
authors.lastname: Davtyan
authors.forename: Steven B
authors.initials: SB
authors.lastname: Housley
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: Anne
authors.initials: A
authors.lastname: Gillies
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Liu
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lee
authors.forename: Marcia N
authors.initials: MN
authors.lastname: Gordon
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000097:blood; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000276:immunology / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D062605:Quillaja Saponins; D012503:Saponins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects; D024801:Tauopathies / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014611:Vaccination / Q000379:methods*; D016875:tau Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D016207:Cytokines; D000939:Epitopes; D005904:Glial Fibrillary Acidic Protein; D062605:Quillaja Saponins; D012503:Saponins; D016875:tau Proteins; C046386:Quil A