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

• Published in: Journal of neurochemistry Vol. 126; no. 4; pp. 473 - 482
• Main Authors: Rasool, Suhail, Martinez‐Coria, Hilda, Wu, Jessica W., LaFerla, Frank, Glabe, Charles G.
• Format: Journal Article
• Language: English
• Published: England 01.08.2013
• Subjects: abeta oligomers; Alzheimer Disease - immunology; Alzheimer Disease - pathology; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - metabolism; amyloid plaques; Animals; Antibodies, Monoclonal - pharmacology; Avoidance Learning; Cognition; Cognition Disorders - immunology; Cognition Disorders - pathology; Cognition Disorders - therapy; Disease Models, Animal; Female; Gene Knock-In Techniques; Maze Learning; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Microglia - immunology; Microglia - pathology; monoclonal antibodies; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Presenilin-1 - genetics; tau pathology; tau Proteins - genetics; Tauopathies - immunology; Tauopathies - pathology; Tauopathies - therapy; vaccination; Vaccination - methods; tau pathology; abeta oligomers; Alzheimer's disease; amyloid plaques; monoclonal antibodies; vaccination
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12305

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. 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. Passive immunization with anti‐oligomeric monoclonal antibodies effectively attenuates cognitive 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.