Scheidt Holger A, Adler Juliane, Zeitschel Ulrike, Höfling Corinna, Korn Alexander, Krueger Martin, Roßner Steffen, Huster Daniel
Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, 04107, Leipzig, Germany.
Paul Flechsig Institute for Brain Research, Leipzig University, Liebigstr. 19, 04103, Leipzig, Germany.
Chemistry. 2017 Nov 7;23(62):15834-15838. doi: 10.1002/chem.201703909. Epub 2017 Oct 10.
The morphology, structure, and dynamics of mature amyloid β (Aβ) fibrils formed by the Aβ variant, which is truncated at residue 11 and chemically modified by enzymatic pyroglutamate formation (pGlu -Aβ(11-40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu -Aβ (11-40) were more toxic than wildtype Aβ (1-40) and the longer pGlu3-Aβ (3-40) especially at higher concentration, whereas the overall morphology was quite similar. The secondary structure of pGlu -Aβ (11-40) fibrils shows the typical two β-strands connected by a short turn as known for mature fibrils of Aβ (1-40) and also pGlu -Aβ (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu -Aβ (11-40) fibrils with wildtype Aβ (1-40), but also a so far not described contact between Gly and Ile . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.
研究了由Aβ变体形成的成熟淀粉样β（Aβ）原纤维的形态、结构和动态，该变体在第11位残基处被截断并通过酶促焦谷氨酸形成（pGlu -Aβ(11 - 40)）进行化学修饰，同时还研究了这些Aβ变体对神经元和星形胶质细胞的毒性。pGlu -Aβ(11 - 40)的原纤维毒性比野生型Aβ(1 - 40)和更长的pGlu3 -Aβ(3 - 40)更大，尤其是在较高浓度时，而总体形态相当相似。pGlu -Aβ(11 - 40)原纤维的二级结构显示出典型的由短转角连接的两条β链，这与Aβ(1 - 40)和pGlu -Aβ(3 - 40)的成熟原纤维相同。对三级接触的进一步研究表明，pGlu -Aβ(11 - 40)原纤维与野生型Aβ(1 - 40)有一些相似之处，但也存在甘氨酸和异亮氨酸之间迄今未描述的接触。这突出了化学修饰对Aβ分子结构的生物学重要性。
