Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability

Genetic evidence predicts a causative role for amyloid-beta (Abeta) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of Abeta are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of Abeta-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and similar to40-fold more than unaggregated peptide, with oligomeric Abeta-(1-42)-induced inhibition significant at 10 nm. Under Abeta-(1-42) oligomer- and fibril-forming conditions, Abeta-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of Abeta-(1-42). We applied the aggregation protocols developed for wild type Abeta-(1-42) to Abeta-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type Abeta-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type Abeta-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar Abeta-(1-42) are useful in distinguishing the structural and functional differences between Abeta-(1-42) and Abeta-(1-40) and genetic mutations of Abeta-(1-42).