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Role of aggregation conditions in structure, stability, and toxicity of intermediates in the A fibril formation pathway

¹ Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843-3122, USA
² Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904, USA
³ Department of Chemical and Biochemical Engineering, University of Maryland, Baltimore County, Baltimore, Maryland 21250, USA

(RECEIVED August 23, 2006; FINAL REVISION December 8, 2006; ACCEPTED December 19, 2006)

-amyloid peptide (A) is one of the main protein components of senile plaques associated with Alzheimer's disease (AD). A readily aggregates to forms fibrils and other aggregated species that have been shown to be toxic in a number of studies. In particular, soluble oligomeric forms are closely related to neurotoxicity. However, the relationship between neurotoxicity and the size of A aggregates or oligomers is still under investigation. In this article, we show that different A incubation conditions in vitro can affect the rate of A fibril formation, the conformation and stability of intermediates in the aggregation pathway, and toxicity of aggregated species formed. When gently agitated, A aggregates faster than A prepared under quiescent conditions, forming fibrils. The morphology of fibrils formed at the end of aggregation with or without agitation, as observed in electron micrographs, is somewhat different. Interestingly, intermediates or oligomers formed during A aggregation differ greatly under agitated and quiescent conditions. Unfolding studies in guanidine hydrochloride indicate that fibrils formed under quiescent conditions are more stable to unfolding in detergent than aggregation associated oligomers or A fibrils formed with agitation. In addition, A fibrils formed under quiescent conditions were less toxic to differentiated SH-SY5Y cells than the A aggregation associated oligomers or fibrils formed with agitation. These results highlight differences between A aggregation intermediates formed under different conditions and provide insight into the structure and stability of toxic A oligomers.

Keywords: Alzheimer's disease; amyloid; aggregation; guanidine hydrochloride; unfolding

Reprint requests to: Theresa Good, Chemical and Biochemical Engineering, UMBC, 1000 Hilltop Circle, Baltimore, MD 21250, USA; e-mail: tgood{at}umbc.edu; fax: (410) 455-1049.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.062514807.

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