Papillomavirus-like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice.
Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Abeta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of Abeta protein repetitively on the viral capsid surface (Abeta-VLP). This Abeta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro. Following Abeta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Abeta deposits in the brain and increased numbers of activated microglia. Furthermore, Abeta-VLP vaccinated mice also showed increased levels of Abeta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Abeta-VLP vaccine induces an effective humoral immune response to Abeta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.
Zamora
Eduardo
E
Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205.
Handisurya
Alessandra
A
Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Shafti-Keramat
Saeed
S
Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Borchelt
David
D
Santa Fe Health Alzheimer's Disease Research Center, Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32611.
Rudow
Gay
G
Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205.
Conant
Katherine
K
Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205.
Cox
Christopher
C
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
Troncoso
Juan C
JC
Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205.
Kirnbauer
Reinhard
R
Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D052688:Bovine papillomavirus 1 / Q000235:genetics* / Q000276:immunology; D036022:Capsid Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002417:Cattle; D016503:Drug Delivery Systems; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014771:Virion / Q000235:genetics* / Q000276:immunology*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D036022:Capsid Proteins; D010446:Peptide Fragments; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C075222:amyloid beta-protein (1-42)