HSV amplicon-mediated Abeta vaccination in Tg2576 mice: differential antigen-specific immune responses.
Given the participation of amyloid beta (Abeta) in Alzheimer's disease (AD) pathogenesis the derivation of experimental therapeutics to prevent Abeta fibrillogenesis and/or enhance removal of parenchymal amyloid deposits represent viable disease-modifying approaches. Active Abeta-based immunotherapies have shown promise in mouse AD models, but application in human trials was accompanied by moderate brain inflammation in a subset of patients. Immune-shaping vaccine platforms may mitigate adverse effects. Herein, we describe the use of herpes simplex virus (HSV)-derived amplicons to elicit distinctive immune responses against Abeta. Two vaccine vectors were constructed: one expressing Abeta1-42 alone (HSVAbeta), and a second expressing Abeta1-42 fused with the molecular adjuvant tetanus toxin Fragment C (HSVAbeta/TtxFC). Peripheral administration of these vaccines augmented humoral responses to Abeta and reduced CNS Abeta deposition in Tg2576 AD mice. Interestingly and unexpectedly, HSVAbeta vaccination was uniquely toxic and incited the expression of pro-inflammatory molecule transcripts within the hippocampi of Tg2576 mice, suggesting that this paradigm may serve as a relevant model to study Abeta vaccine-elicited CNS inflammatory syndromes.
Bowers
William J
WJ
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
Mastrangelo
Michael A
MA
Stanley
Hilary A
HA
Casey
Ann E
AE
Milo
Lawrence J
LJ
Federoff
Howard J
HJ
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D000686:Amyloidosis / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000276:immunology; D002452:Cell Count / Q000379:methods; D002460:Cell Line; D006224:Cricetinae; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000627:therapeutic use; D007150:Immunohistochemistry / Q000379:methods; D016233:Immunotherapy, Active / Q000379:methods*; D007372:Interferons / Q000145:classification / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018139:Simplexvirus / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D013744:Tetanus Toxin / Q000276:immunology / Q000627:therapeutic use; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000941:Antigens; D007132:Immunoglobulin Isotypes; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D012333:RNA, Messenger; D013744:Tetanus Toxin; C075222:amyloid beta-protein (1-42); C040635:tetanus toxin fragment C; D007372:Interferons