A novel recombinant 6Aß15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer's disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. Targeting amyloid-ß (Aß) may be currently the most promising immunotherapeutic strategy for AD. In this study, a recombinant chimeric 6Aß15-THc-C immunogen was formulated with alum adjuvant as a novel Aß B-cell epitope candidate vaccine (rCV02) for AD. We examined its efficacy in preventing the cognitive deficit and synaptic impairment in 3 × Tg-AD mice. Using a toxin-derived carrier protein, the rCV02 vaccine elicited robust Aß-specific antibodies that markedly reduced AD-like pathology and improved behavioral performance in 3 × Tg-AD mice. Along with the behavioral improvement in aged 3 × Tg-AD mice, rCV02 significantly decreased calpain activation concurrent with reduced soluble Aß or oligomeric forms of Aß, probably by preventing dynamin 1 and PSD-95 degradation. Our data support the hypothesis that reducing Aß levels in rCV02-immunized AD mice increases the levels of presynaptic dynamin 1 and postsynaptic PSD-95 allowing functional recovery of cognition. In conclusion, this novel and highly immunogenic rCV02 shows promise as a new candidate prophylactic vaccine for AD and may be useful for generating rapid and strong Aß-specific antibodies in AD patients with pre-existing memory Th cells generated after immunization with conventional tetanus toxoid vaccine.

'Clinical trials in Alzheimer's disease': immunotherapy approaches.

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid ß (Aß) peptide represents an important molecular target for intervention in Alzheimer's disease. Several types of Aß peptide immunotherapy for Alzheimer's disease are under investigation, direct immunization with synthetic intact Aß(42) , active immunization involving the administration of synthetic fragments of Aß peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aß peptide. Pre-clinical studies showed that immunization against Aß peptide can provide protection and reversal of the pathology of Alzheimer's disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aß peptide immunotherapy approaches are under investigation but also against tau pathology.

Amyloid beta peptides with an additional cysteine residue can enhance immunogenicity and reduce the amyloid beta burden in an Alzheimer's disease mouse model.

For the development of a safe vaccine for Alzheimer's disease (AD), we studied the immunogenicity of amyloid beta (Abeta) peptides without adjuvant. Addition of a cysteine residue (Cys) to Abeta peptides enhanced immunogenicity in mice compared to those without Cys. Vaccination with the Abeta-Cys peptides reduced Abeta deposits in AD model mice. From these results, the Abeta-Cys peptides, administered without adjuvant, are considered candidates for vaccine therapy for AD.