Antibody 9D5 recognizes oligomeric pyroglutamate amyloid-β in a fraction of amyloid-β deposits in Alzheimer's disease without cross-reactivity with other protein aggregates.
Recent evidence suggests that soluble oligomeric amyloid-β (Aβ) 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 AβpE3 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 Aβ antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent Aβ 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 Aβ deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total Aβ 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 AβpE3 of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of Aβ deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits.
Division of Molecular Psychiatry, Georg-August-University, University Medicine Göttingen, Göttingen, Germany.
Vivek
V
Venkataramani
Oliver
O
Wirths
Herbert
H
Budka
Wolfgang
W
Härtig
Gabor G
GG
Kovacs
Thomas A
TA
Bayer
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D000704:Analysis of Variance; D000906:Antibodies / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011328:Prions / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000276:immunology*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000906:Antibodies; D004268:DNA-Binding Proteins; D016056:Immunodominant Epitopes; D011328:Prions; D051844:alpha-Synuclein; D016875:tau Proteins; D011761:Pyrrolidonecarboxylic Acid