Pyroglutamate amyloid beta 3-42 (pGlu-Aβ3-42)

Pyroglutamate amyloid beta 3-42 (pGlu-Aβ3-42) is a highly neurotoxic and aggregation-prone variant of the amyloid beta peptide, characterized by the conversion of an N-terminal glutamate residue into pyroglutamate (PMID: 22553031). This modification, catalyzed by the enzyme glutaminyl cyclase, typically occurs after the truncation of the full-length Aβ1-42 peptide (Journal of Biological Chemistry, DOI: 10.1074/jbc.M111.250779). pGlu-Aβ3-42 is a major component of senile plaques in the brains of patients with Alzheimer's disease and is notably absent from the brains of healthy individuals. Due to its increased hydrophobicity and resistance to degradation, it acts as a potent seed for the rapid accumulation of other amyloid species, leading to synaptic loss and neuronal death (Nature Communications, DOI: 10.1038/ncomms11555). Therapeutic strategies targeting this specific isoform, such as the monoclonal antibody donanemab, aim to selectively clear deposited plaques while sparing soluble Aβ monomers (New England Journal of Medicine, DOI: 10.1056/NEJMoa2100708). By focusing on this pathological species, these treatments seek to slow cognitive decline and modify the underlying progression of neurodegenerative disease.

Other names

N3pE-amyloid betapE3-AβAβpE3-42Pyroglutamate-modified amyloid betaN-terminal truncated pyroglutamate-modified amyloid-β

Monoclonal antibodies bind specifically to the N-terminal pyroglutamate epitope of the truncated amyloid beta peptide, facilitating the clearance of existing amyloid plaques through microglial-mediated phagocytosis.