Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability
Karie N. Dahlgren, Arlene M. Manelli, W. Blaine Stine, Jr, Lorinda K. Baker, Grant A. Krafft, and Mary Jo LaDu
The Journal of Biological Chemistry (2002) Vol. 277, No. 35, 32046–32053

ABSTRACT:  Genetic evidence predicts a causative role for amyloid-β (Aβ) in Alzheimer’s disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of Ab 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 Aβ(1–42).  Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ~40-fold more than unaggregated peptide, with oligomeric Aβ(1–42)-induced inhibition significant at 10 nM. Under Aβ(1–42) oligomer-and fibril-forming conditions, Ab(1–40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of Aβ(1–42). We applied the aggregation protocols developed for wild type Aβ(1–42) to Aβ(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 Aβ(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 Aβ(1–42) fibril preparations.  These data demonstrate that protocols developed to produce oligomeric and fibrillar Aβ(1–42) are useful in distinguishing the structural and functional differences between Aβ(1–42) and Aβ(1–40) and genetic mutations of Aβ(1– 42).