N-terminal pyroglutamate-modified amyloid beta (pGlu3-Aβ)

N-terminal pyroglutamate-modified amyloid beta (pGlu3-Aβ) is a truncated and post-translationally modified variant of the amyloid beta peptide, formed through the cyclization of an N-terminal glutamate residue at position 3 by the enzyme glutaminyl cyclase (QC) (Source: PubMed, PMID: 22103437). This modification renders the peptide highly hydrophobic, resistant to degradation by peptidases, and significantly more neurotoxic than full-length Aβ1-40 or Aβ1-42 (Source: NIH, National Institute on Aging). pGlu3-Aβ is a major component of filamentous amyloid plaques in Alzheimer's disease and acts as a "seed" for the rapid aggregation of other amyloid species (Source: Journal of Biological Chemistry). Because this specific pGlu3 epitope is found almost exclusively in pathological plaque deposits and not in physiological soluble Aβ, it serves as a highly specific target for immunotherapy. Monoclonal antibodies such as donanemab (LY3002813) have been developed to bind this epitope, facilitating the clearance of established plaques via microglial phagocytosis (Source: Eli Lilly and Company; New England Journal of Medicine). Therapeutic intervention targeting pGlu3-Aβ is currently a leading strategy for slowing cognitive decline in patients with early symptomatic Alzheimer's disease.

Other names

AβpE3pE3-AβPyroglutamate-amyloid betaN3pE-amyloid betaAmyloid beta (3-42) pyroglutamate

Monoclonal antibody binding to the N-terminal pyroglutamate epitope of amyloid beta, which triggers Fc-receptor mediated phagocytosis by microglia to clear existing amyloid plaques from the brain parenchyma (Source: Nature, doi:10.1038/s41586-021-03547-x).