Amyloid-β protofibrils: size, morphology and synaptotoxicity of an engineered mimic

Anatoly Dubnovitsky, Anders Sandberg, M Mahafuzur Rahman, Iryna Benilova, Christofer Lendel, Torleif Härd
PloS One 2013, 8 (7): e66101
Structural and biochemical studies of the aggregation of the amyloid-β peptide (Aβ) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of Aβ called Aβcc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of Aβ42cc protofibrils. Like wild type Aβ they appear as smooth rod-like particles with a diameter of 3.1 (±0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. Aβ42cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put Aβ42cc protofibrils into the same class of species as fibrillar oligomers of wild type Aβ. Aβ42cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, Aβ42cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by Aβ42cc and aggregates of wild type Aβ42. We suggest that Aβ42cc protofibrils may be used in research and applications that require stable preparations of protofibrillar Aβ.

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