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 (pGlu₁₁ -Aβ(11-40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu₁₁ -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 pGlu₁₁ -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 pGlu₃ -Aβ (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu₁₁ -Aβ (11-40) fibrils with wildtype Aβ (1-40), but also a so far not described contact between Gly₂₅ and Ile₃₁ . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.

Keywords: Alzheimer's disease; amyloid; pyroglutamyl-modification; secondary structure.