Systemic vaccination with anti‐oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg‐AD mice

Abstract

Alzheimer’s disease (AD) is a devastating disorder that is clinically characterized by a comprehensive cognitive decline. Accumulation of the amyloid-beta (Aβ) peptide plays a pivotal role in the pathogenesis of AD. In AD, the conversion of Aβ from a physiological soluble monomeric form into insoluble fibrillar conformation is an important event. The most toxic form of Aβ is oligomers, which is the intermediate step during the conversion of monomeric form to fibrillar form. There are at least two types of oligomers: oligomers that are immunologically related to fibrils and those that are not. In transgenic AD animal models, both active and passive anti-Aβ immunotherapies improve cognitive function and clear the parenchymal accumulation of amyloid plaques in the brain. In this report we studied effect of immunotherapy of two sequence-independent non-fibrillar oligomer specific monoclonal antibodies on the cognitive function, amyloid load and tau pathology in 3xTg-AD mice. Anti-oligomeric monoclonal antibodies significantly reduce the amyloid load and improve the cognition. The clearance of amyloid load was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies effectively attenuates behavioral and pathological impairments in 3xTg-AD mice. These findings demonstrate the potential of using oligomer specific monoclonal antibodies as a therapeutic approach to prevent and treat Alzheimer’s disease.

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

“…It is during this latter period that ExoY's actions are likely to be the most debilitating, hindering migration, proliferation, and tissue repair after infection (63). Our data would support the idea that extracellular high-molecular-weight endothelial tau is a target for therapy (25,50). However, following infection, none of the antibodies tested provided protection against the injurious supernatant, likely because of the antibodies' inability to capture and remove the potentially injurious high-molecularweight tau species from the supernatant or the antibodies' success in removing some cytoprotective species.…”

“…We then tested the Tau-5 and TauC3 antibodies, neither of which conferred protection (data not shown). Thus it is unlikely that these antibodies have therapeutic potential in infectious forms of proteinopathy (25,50).…”

“…Monoclonal antibodies targeting tau oligomers have been reported to possess therapeutic potential in various proteinopathy models (50). We therefore tested whether three independent tau antibodies, TOC1, Tau-5, and TauC3 antibodies, confer protection against the injurious supernatant.…”

Prion-like Properties of Tau Protein: The Importance of Extracellular Tau as a Therapeutic Target

“…A␤ oligomers, and there have now been multiple antibodies and studies related to detection and targeting of these species (64). This approach has also been applied to Tau, in which an oligomer-specific polyclonal antibody was developed (58). Multiple active and passive vaccine studies have now targeted intracellular proteins (56,57,59,60,(65)(66)(67), and most recently, a cell-based aggregate seeding assay was used to prioritize anti-Tau antibodies prior to testing in vivo (61).…”

“…This produced demonstrable benefits, although at this time it was not appreciated that the vaccine might have worked by targeting extracellular ␣-synuclein (56). Since then, multiple active and passive vaccination studies have been carried out against Tau, with variable results (57)(58)(59)(60)(61). It is now fairly well accepted that antibodies against pathological proteins can ameliorate pathology in transgenic mouse models.…”