Antibody 9D5 Recognizes Oligomeric Pyroglutamate Amyloid-beta in a Fraction of Amyloid-beta Deposits in Alzheimer's Disease without Cross-Reactivity with other Protein Aggregates

Abstract

Recent evidence suggests that soluble oligomeric amyloid-beta (A beta) assemblies are critically involved in the pathogenesis of Alzheimer's disease (AD). We have generated a conformation-dependent monoclonal antibody (9D5) that selectively recognizes low-molecular weight A beta(pE3) oligomers, and demonstrated its diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a spectrum of neurodegeneration-related protein deposits for cross-reactivity, and by comparing the staining pattern of 9D5 with a generic A beta antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent A beta antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5 antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43 inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the specificity of 9D5 for A beta deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total A beta plaque load in the entorhinal cortex, the CA1 region, and the temporal neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of an epitope found only in oligomeric assemblies of A beta(pE3) of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of A beta deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits.