Authors

Koichi Iijima, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PAFollow
Hsueh-Cheng Chiang, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; Department of Neurobiology and Behavior, State University of New York, Stony Brook, NY
Stephen A Hearn, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Inessa Hakker, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Anthony Gatt, Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA
Christopher Shenton, Laboratory of Neurogenetics and Protein Misfolding Diseases, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PAFollow
Linda Granger, Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PAFollow
Amy Leung, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Kanae Iijima-Ando, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; Laboratory of Neurogenetics and Protein Misfolding Diseases, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PAFollow
Yi Zhong, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

Document Type

Article

Publication Date

2-1-2008

Comments

This article has been peer reviewed and is published in PLoS One 2008, 3(2). The published version is available at DOI: 10.1371/journal.pone.0001703. © Public Library of Science

Abstract

Aggregation of the amyloid-beta-42 (Abeta42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Abeta aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Abeta can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Abeta42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Abeta42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Abeta42Arc) and an artificial mutation (Abeta42art) that is known to suppress aggregation and toxicity of Abeta42 in vitro. In the Drosophila brain, Abeta42Arc formed more oligomers and deposits than did wild type Abeta42, while Abeta42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Abeta peptides. Surprisingly, however, Abeta42art caused earlier onset of memory defects than Abeta42. More remarkably, each Abeta induced qualitatively different pathologies. Abeta42Arc caused greater neuron loss than did Abeta42, while Abeta42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin S-stained Abeta aggregates: Abeta42Arc formed large deposits in the cell body, Abeta42art accumulated preferentially in the neurites, while Abeta42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Abeta42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.

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