Identification of Low Molecular Weight Pyroglutamate Aβ Oligomers in Alzheimer Disease A NOVEL TOOL FOR THERAPY AND DIAGNOSIS

N-terminally truncated A beta peptides starting with pyroglutamate (A beta pE3) represent a major fraction of all A beta peptides in the brain of Alzheimer disease (AD) patients. A beta pE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length A beta. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of A beta pE3 and studied the potential involvement of oligomeric A beta pE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall A beta plaque load and A beta pE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight A beta pE3 oligomers.