Pyroglutamate-3 amyloid-beta (AβpE3)

Pyroglutamate-3 amyloid-beta (AβpE3) is a highly neurotoxic, N-terminally truncated, and chemically modified form of the amyloid-beta peptide found in the brains of patients with Alzheimer's disease. It is formed through the dehydration of an N-terminal glutamate residue at position 3 into pyroglutamate, a reaction catalyzed by the enzyme glutaminyl cyclase (Source: PMID: 22103434). This modification increases the peptide's hydrophobicity, resistance to degradation, and propensity to form stable, toxic oligomers that act as seeds for the rapid accumulation of other amyloid-beta variants into insoluble plaques (Source: PMID: 20471434). Unlike full-length Aβ, AβpE3 is almost exclusively located within pathological brain deposits rather than in the blood or cerebrospinal fluid, making it a highly specific target for immunotherapy. Therapeutic strategies, such as the monoclonal antibody Donanemab, specifically bind to this epitope to facilitate the clearance of established plaques by the immune system, aiming to slow cognitive decline in early-stage Alzheimer's patients (Source: PMID: 37459331).

Other names

pGlu-AβN3pE-amyloid betaPyroglutamate-modified amyloid-beta proteinAβ3(pE)-42pGlu3-Aβ

Monoclonal antibodies specifically target the N-terminal pyroglutamate epitope of the modified amyloid-beta peptide, which is found exclusively in deposited plaques, to trigger microglial-mediated phagocytosis and clearance of existing amyloid deposits from the brain (Source: PMID: 34125048, PMID: 37459331).