Pyroglutamate‐Modified Amyloid β (11‐ 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar

Abstract 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 11 ‐Aβ(11–40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu 11 ‐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 11 ‐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 3 ‐Aβ (3–40). Further insights into tertiary contacts exhibit some similarities of pGlu 11 ‐Aβ (11–40) fibrils with wildtype Aβ (1–40), but also a so far not described contact between Gly 25 and Ile 31 . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.