Self-Assembly of Aβ1 - 42 into Globular Neurotoxins

• Published in: Biochemistry (Easton) Vol. 42; no. 44; pp. 12749 - 12760
• Main Authors: Chromy, Brett A, Nowak, Richard J, Lambert, Mary P, Viola, Kirsten L, Chang, Lei, Velasco, Pauline T, Jones, Bryan W, Fernandez, Sara J, Lacor, Pascale N, Horowitz, Peleg, Finch, Caleb E, Krafft, Grant A, Klein, William L
• Format: Journal Article
• Language: English
• Published: American Chemical Society 11.11.2003
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi030029q

Amyloid β 1−42 (Aβ1 - 42) is a self-associating peptide that becomes neurotoxic upon aggregation. Toxicity originally was attributed to the presence of large, readily formed Aβ fibrils, but a variety of other toxic species are now known. The current study shows that Aβ1 - 42 can self-assemble into small, stable globular assemblies free of fibrils and protofibrils. Absence of large molecules was verified by atomic force microscopy (AFM) and nondenaturing gel electrophoresis. Denaturing electrophoresis revealed that the globular assemblies comprised oligomers ranging from trimers to 24mers. Oligomers prepared at 4 °C stayed fibril-free for days and remained so when shifted to 37 °C, although the spectrum of sizes shifted toward larger oligomers at the higher temperature. The soluble, globular Aβ1 - 42 oligomers were toxic to PC12 cells, impairing reduction of MTT and interfering with ERK and Rac signal transduction. Occasionally, oligomers were neither toxic nor recognized by toxicity-neutralizing antibodies, suggesting that oligomers could assume alternative conformations. Tests for oligomerization-blocking activity were carried out by dot-blot immunoassays and showed that neuroprotective extracts of Ginkgo biloba could inhibit oligomer formation at very low doses. The observed neurotoxicity, structure, and stability of synthetic Aβ1 - 42 globular assemblies support the hypothesis that Aβ1 - 42 oligomers play a role in triggering nerve cell dysfunction and death in Alzheimer's disease.