Pyroglutamyl-amyloid beta (pGlu-Aβ)

Pyroglutamyl-amyloid beta (pGlu-Aβ) is a post-translationally modified form of the amyloid-beta peptide that is highly neurotoxic and prone to aggregation (Source 1.2.3). It is formed through the N-terminal truncation of amyloid-beta followed by the cyclization of the third glutamate residue, a process catalyzed by the enzyme glutaminyl cyclase (Source 1.1.1, 1.2.1). This modification increases the peptide's hydrophobicity and resistance to proteolytic degradation, allowing it to act as a potent seed for the formation of insoluble amyloid plaques in the brains of Alzheimer's disease patients (Source 1.2.3, 1.5.1). Unlike full-length amyloid-beta, pGlu-Aβ is almost exclusively found in pathological deposits, making it a highly specific therapeutic target (Source 1.2.2, 1.3.2). Therapeutic strategies include the use of monoclonal antibodies, such as donanemab, which bind specifically to the pGlu-Aβ epitope to facilitate the clearance of plaques by the brain's immune cells (Source 1.2.3, 1.3.2). While targeting pGlu-Aβ has shown success in reducing plaque burden and slowing cognitive decline in clinical trials, it is associated with safety concerns like amyloid-related imaging abnormalities (ARIA) (Source 1.2.3, 1.6.2). The development of ultra-sensitive assays for pGlu-Aβ in plasma and cerebrospinal fluid also offers potential for its use as a biomarker for early disease detection and monitoring of treatment efficacy (Source 1.4.2, 1.6.3).

Other names

AβpE3pE3-AβN3pE-AβPyroglutamate-modified amyloid-betapGlu-AbetapGlu3-AβN3pE-amyloid beta

Monoclonal antibodies bind to the N-terminal pyroglutamate epitope of aggregated amyloid-beta, triggering Fc-receptor mediated phagocytosis by microglia to clear existing plaques.