Spot the Difference: Function versus Toxicity in Amyloid Fibrils

Abstract

In a recent study, Hervas et al. extracted Orb2 fibrils, that are involved in long-term memory formation, from Drosophila brains, characterised their function, and determined their structure using cryo-electron microscopy (cryo-EM). The fibrils show a remarkable resemblance to amyloid β (Aβ) fibrils associated with Alzheimer's disease, highlighting the subtle difference between functional and dysfunctional amyloid.

Keywords: Alzheimer; CPEB; Orb2; amyloid; cryo-electron microscopy; memory.

Figure 1. Comparison between the Functional Amyloid Fold of Orb2 (PDB: 6VPS) (Left) versus the Toxic Fibril Architecture of Aβ₄₀ (PDB: 2M4J) (Right).

Whereas Orb2 is involved in long-term memory formation, Aβ₄₀ is involved in the neurodegenerative disorder Alzheimer’s disease. Both structures (one from Drosophila brain and one from human brain) have C3 symmetry with three protofilaments (highlighted in yellow, green, and pink) that form the mature fibril. Whereas the core of Orb2 is mainly hydrophilic (blue), the Aβ₄₀ core is hydrophobic (red). In addition, for Aβ₄₀ nearly the whole protein is structured in the fibril core (red bar), whereas for Orb2 the majority of the protein sequence is dynamically disordered (grey bar) allowing functionally important interactions with other molecules.