Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Abstract

In transgenic animal models, humoral immunity directed against the β-amyloid peptide (Aβ), which is deposited in the brains of AD patients, can reduce Aβ plaques and restore memory. However, initial clinical trials using active immunization with Aβ1–42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Aβ. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Aβ (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Aβ retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Aβ retroparticles evoked high and long-lived Aβ-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Aβ plaque load to ∼60% of controls and lowered both insoluble Aβ40 as well as Aβ42 in APP23 brain, but also significantly reduced cerebral soluble Aβ species. In summary, Aβ retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer’s disease.

The Receptor Attachment Function of Measles Virus Hemagglutinin Can Be Replaced with an Autonomous Protein That Binds Her2/ neu While Maintaining Its Fusion-Helper Function

“…Based on previous work we decided to use the platelet-derived growth factor receptor (PDGFR) transmembrane domain, which becomes efficiently incorporated into retrovirus particles and can be fused to proteins or peptides of choice (34,35). Fusion of the reading frame of the Her2/neuspecific DARPin 9.29 (27) to the PDGFR transmembrane domain resulted in the construct pDisplay-D 9.29 (Fig.…”

Virus-like particle based vaccines for Alzheimer disease

“…47 In 2009, using engineered MLV retroparticle VLPs displaying Ab 1-15 , Bach and colleagues showed that a single dose of vaccine without adjuvant elicited high titers of anti-Ab antibodies in APP mice. 48 Immunization resulted in a statistically significant ∼40% reduction in plaque area and number in the brain as compared to nonvaccinated control mice. Recently, we showed that immunization with Qb bacteriophage VLPs conjugated with peptides representing Ab 1-9 or Ab 28-40 resulted in hightiter antibody responses and significant reductions (40-70% depending on the assay) of Ab deposition in the brains of APP mice.…”

“…53 Accordingly, immunization with HPV, Qb bacteriophage and MLV VLPs displaying short (9-16 amino acid) peptides derived from the N-terminus of Ab does not induce T-cell proliferative responses against Ab. 48,53 Efficacy of VLP-based vaccines in the APP mouse model. Three studies have examined the effectiveness of vaccination with VLP-based immunogen targeting Ab in various APP mouse models.…”

“…47 Similar data were generated in APP Tg mice using recombinant Murine Leukemia Virus (MLV) VLPs displaying Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and Qb bacteriophage VLPs chemically conjugated with Ab [1][2][3][4][5][6][7][8][9] or Ab 28-40 peptides. 48,49 In APP Tg mice, antibodies induced by MLV-and Qb-VLP based immunogens were by and large of the IgG1 and IgG2b subtypes, indicative of an anti-inflammatory T helper (Th) 2 response.…”

Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies

“…When 1 × 10 10 particles were injected intravenously in APP23 mice, they produced high titers of anti-Aβ antibodies, and the subtypes were IgG1 and IgG2b. The immunized mice showed significant reduction of SPs, soluble and insoluble Aβ (Bach et al 2009). Each virus-like particle expresses several thousands epitopes of A β 1-15 and the injected particles were calculated as containing 150 ng of Aβ 1-15.…”