Pyroglutamate-3 amyloid-β (AβpE3) (AβpE3)

Pyroglutamate-3 amyloid-β (AβpE3) is an N-terminally truncated and modified form of the amyloid-β peptide, generated by removal of Asp-1 and Ala-2 followed by cyclization of Glu-3 to pyroglutamate via glutaminyl cyclase (QC). This modification confers increased aggregation propensity, resistance to proteolysis, and heightened neurotoxicity compared to full-length Aβ, promoting formation of toxic oligomers and fibrils that seed plaques in Alzheimer's disease (AD) brains, where it constitutes over 60% of N-truncated Aβ species. AβpE3 deposits early in diffuse plaques, focal plaques, and cerebral amyloid angiopathy in human AD, Down syndrome, and nonhuman primates, often colocalizing with general Aβ. It inhibits full-length Aβ fibrillogenesis, favoring more toxic oligomeric states, and induces neuronal apoptosis, inflammation, and membrane damage. Therapeutic strategies target AβpE3 directly with high-affinity monoclonal antibodies (e.g., c#6, c#17, c#24; KD 1-10 nM) that bind the pE3-Phe4 "head" to inhibit aggregation, or indirectly via QC inhibitors like P150/03 to reduce its formation, showing reduced plaques and improved cognition in models. Plasma AβpE3 serves as a biomarker for brain amyloid pathology. Structural studies reveal distinct antibody binding modes exploiting the hydrophobic pE3 modification for specificity.

Other names

pyroGlu-3 AβAβN3(pE)pE3-AβpyroGlu-3 amyloid-βpGlu-Aβ3–42AβpE3

Inhibition of fibril formation; prevention of pyroglutamate formation by QC inhibition; binding to pE3 N-terminus to block aggregation