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J. Biol. Chem., Vol. 280, Issue 41, 35069-35076, October 14, 2005

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Sequence Determinants of Enhanced Amyloidogenicity of Alzheimer A42 Peptide Relative to A40^*

From the Department of Chemistry, Princeton University, Princeton, New Jersey 08544

Aggregation of proteins into insoluble deposits is associated with a variety of human diseases. In Alzheimer disease, the aggregation of amyloid (A) peptides is believed to play a key role in pathogenesis. Although the 40-mer (A40) is produced in vivo at higher levels than the 42-mer (A42), senile plaque in diseased brains is composed primarily of A42. Likewise, in vitro, A42 forms fibrils more rapidly than A40. The enhanced amyloidogenicity of A42 could be due simply to its greater length. Alternatively, specific properties of residues Ile⁴¹ and Ala⁴² might favor aggregation. To distinguish between these two possibilities, we constructed a library of sequences in which residues 41 and 42 were randomized. The aggregation behavior of the resulting sequences was assessed using a high throughput screen, based on the finding that fusions of A42 to green fluorescence protein (GFP) prevent the folding and fluorescence of GFP, whereas mutations in A42 that disrupt aggregation produce green fluorescent fusions. Correlations between the sequences of A42 mutants and the fluorescence of A42-GFP fusions in vivo were confirmed in vitro through biophysical studies of synthetic 42-residue peptides. The data reveal a strong correlation between aggregation propensity and the hydrophobicity and -sheet propensities of residues at positions 41 and 42. Moreover, several mutants containing hydrophilic residues and/or -sheet breakers at positions 41 and/or 42 were less prone to aggregate than A40 wherein these two residues are deleted entirely. Thus, properties of the side chains at positions 41 and 42, rather than length per se, cause A42 to aggregate more readily than A40.

Received for publication, May 26, 2005 , and in revised form, August 2, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 609-258-2901; Fax: 609-258-6746; E-mail: hecht{at}princeton.edu.

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				W. Kim and M. H. Hecht Generic hydrophobic residues are sufficient to promote aggregation of the Alzheimer's Abeta42 peptide PNAS, October 24, 2006; 103(43): 15824 - 15829. [Abstract] [Full Text] [PDF]