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In Vitro Characterization of Conditions for Amyloid-β Peptide Oligomerization and Fibrillogenesis

2003; Elsevier BV; Volume: 278; Issue: 13 Linguagem: Inglês

10.1074/jbc.m210207200

1083-351X

W. Blaine Stine, Karie N. Dahlgren, Grant A. Krafft, Mary Jo LaDu,

S100 Proteins and Annexins

Extensive research causally links amyloid-β peptide (Aβ) to Alzheimer's disease, although the pathologically relevant Aβ conformation remains unclear. Aβ spontaneously aggregates into the fibrils that deposit in senile plaques. However, recent in vivo and in vitro reports describe a potent biological activity for oligomeric assemblies of Aβ. To consistently prepare in vitro oligomeric and fibrillar forms of Aβ1–42, a detailed knowledge of how solution parameters influence structure is required. This manuscript represents the first study using a single chemically and structurally homogeneous unaggregated starting material to demonstrate that the formation of oligomers, fibrils, and fibrillar aggregates is determined by time, concentration, temperature, pH, ionic strength, and Aβ species. We recently reported that oligomers inhibit neuronal viability 10-fold more than fibrils and ∼40-fold more than unaggregated peptide, with oligomeric Aβ1–42-induced neurotoxicity significant at 10 nm. In addition, we were able to differentiate by structure and neurotoxic activity wild-type Aβ1–42 from isoforms containing familial mutations (Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., and LaDu, M. J. (2002) J. Biol. Chem. 277, 32046–32053). Understanding the biological role of specific Aβ conformations may define the link between Aβ and Alzheimer's disease, re-focusing therapeutic approaches by identifying the pernicious species of Aβ ultimately responsible for the cognitive dysfunction that defines the disease.