H. Buniatian Institute of Biochemistry of Armenian NAS, Yerevan 0014, Armenia.
Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle, Germany.
Neurochem Int. 2018 Feb;113:112-119. doi: 10.1016/j.neuint.2017.12.001. Epub 2017 Dec 7.
Compelling evidence suggests a crucial role of amyloid beta peptides (Aβ(1-40/42)) in the etiology of Alzheimer's disease (AD). The N-terminal truncation of Aβ(1-40/42) and their modification, e.g. by glutaminyl cyclase (QC), is expected to enhance the amyloid toxicity. In this work, the MALDI-TOF mass spectrometry application proved N-terminal cleavage of Aβ(1-40/42) by purified dipeptidyl peptidase IV (DPPIV) in vitro observed earlier. The subsequent transformation of resulted Aβ(3-40/42) to pE-Aβ(3-40/42) in QC catalyzed glutamate cyclization was manifested. Hence, consecutive conversion of Aβ(1-40/42) by DPPIV and QC can be assumed as a potential mechanism of formation of non-degrading pyroglutamated pE-Aβ(3-40/42), which might accumulate and contribute to AD progression. The in vitro acceleration of Aβ(1-40) aggregation in the simultaneous presence of DPPIV and QC was shown also.
有充分证据表明β淀粉样肽（Aβ(1-40/42)）在阿尔茨海默病（AD）的发病机制中起着关键作用。Aβ(1-40/42)的 N 端截断及其修饰，例如通过谷氨酰胺酰氨酶（QC），预计会增强淀粉样毒性。在这项工作中，MALDI-TOF 质谱应用证明了先前在体外观察到的纯化二肽基肽酶 IV（DPPIV）对 Aβ(1-40/42)的 N 端切割。随后在 QC 催化的谷氨酸环化作用下，生成的 Aβ(3-40/42)转化为 pE-Aβ(3-40/42)。因此，可以假定 Aβ(1-40/42)通过 DPPIV 和 QC 的连续转化是形成非降解性焦谷氨酸化 pE-Aβ(3-40/42)的潜在机制，这种 pE-Aβ(3-40/42)可能会积累并促进 AD 的进展。还显示了同时存在 DPPIV 和 QC 时 Aβ(1-40)聚集的体外加速。
