Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease

Abstract

Pyroglutamate-modified amyloid-β (Aβ(pE3)) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of Aβ(pE3-42) show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of Aβ(pE3). In this minireview, we summarize the current knowledge on Aβ(pE3), discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.

FIGURE 1.

Generation of pyroglutamate Aβ. The first N-terminal two amino acids, aspartate and alanine, are cleaved off by an unknown mechanism, exposing glutamate at position 3 of the N terminus of Aβ. Subsequently, glutamate is post-translationally modified to N-terminal pyroglutamate (pE) by dehydration catalyzed by QC activity. The novel peptide has altered biochemical properties with severe pathological consequences. The enhanced toxicity is likely due to the higher aggregation propensity and the longer bioavailability of the Aβ_pE3 oligomers.

FIGURE 2.

Schematic of the hypothesized toxic cascade of pyroglutamate Aβ in AD and potential therapeutic interventions. After N-terminal truncation of the first two amino acid residues of the full-length Aβ_1–40/42 monomers (Aβ_1–x), QC activity catalyzes the formation of Aβ_pE3–x monomers either intracellularly or extracellularly. The Aβ_pE3–x monomers are highly prone to rapid oligomerization and fibrillization. Oligomers may act as seeds for full-length Aβ precipitating in plaques and blood vessels. As Aβ_pE3–x oligomers are detected in microglia and human blood (51), it is likely that the oligomers are cleared by these routes. Therapeutic effects were achieved by reducing QC activity, thereby inhibiting the cyclization of Aβ_3–x, and by passive immunization with the 9D5 antibody against low molecular weight Aβ_pE3–x oligomers.