N-truncated pyroglutamate amyloid-beta (pGlu-Aβ)

N-truncated pyroglutamate amyloid-beta (pGlu-Aβ) is a post-translationally modified form of the amyloid-beta peptide that serves as a major constituent of insoluble neuritic plaques in Alzheimer's disease. It is formed when the N-terminal of the Aβ peptide is truncated, followed by the cyclization of the glutamate residue at position 3 into pyroglutamate, a process catalyzed by the enzyme glutaminyl cyclase (QC). This modification increases the peptide's hydrophobicity and resistance to degradation, making it significantly more neurotoxic and prone to aggregation than standard Aβ1-42. pGlu-Aβ acts as a potent seed for the accumulation of other amyloid species, accelerating the stabilization of plaques within the brain. Because this specific isoform is found almost exclusively in pathological deposits and is absent from the soluble Aβ pool in healthy individuals, it is a highly selective therapeutic target. Monoclonal antibodies like donanemab are designed to recognize the pGlu-Aβ epitope to facilitate the clearance of existing plaques via microglial phagocytosis, with the goal of slowing clinical decline in neurodegenerative disease.

Other names

pGlu-AbetaAβpE3Pyroglutamate-modified amyloid betaN3pE-AβAβpE3-42Amyloid-beta pE3-42

Targeted immunotherapy using monoclonal antibodies that bind to the N-terminal pyroglutamate residue, triggering Fc-receptor-mediated phagocytosis by microglia to clear insoluble amyloid plaques from the brain parenchyma.