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Neuritic plaques of Alzheimer patients are composed of multiple protein components. Among them, the amyloid β-peptides (Aβ) 1–40/42 and further N- and C-terminally modified fragments of Aβ are highly abundant. Most prominent are the isoaspartate (isoAsp)-Aβ peptides and pyroglutamyl (pGlu)-Aβ. While pGlu-Aβ can only be formed from an N-terminal glutamate by glutaminyl cyclase, spontaneous isoAsp-isomerization cannot occur at an N-terminal aspartate of peptides. This means that isoAsp-Aβ formation must precede proteolysis of the amyloid precursor protein (APP). Aβ generation from APP by β- and γ-secretases initiates the amyloid peptide aggregation and deposition process. Two aspartate proteases have been identified as secretases: BACE-1 (β-site amyloid precursor protein cleaving enzyme) and the intramembrane γ-secretase multiprotein complex. However, recent evidence supports more than one β-secretase initiating this cascade. Formation of Aβ1–40/42 was predominantly studied by expression of mutated human APP sequences in cell culture and transgenic animals, generating Aβ fragments that did not contain such multiple posttranslational modifications as in Alzheimer's disease. This prompted us to investigate the catalytic turnover of Asp- or isoAsp-containing APP-derived peptide sequences by BACE-1 and cathepsin B, another potential β-secretase. While cathepsin B is more effective than BACE-1 in processing the Asp-containing peptide derivatives, only cathepsin B can cleave the isoAsp-containing peptides, which occurs with high catalytic efficiency.

Isoaspartate-containing amyloid precursor protein-derived peptides alter efficacy and specificity of potential β-secretases