A beta 42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila

Iijima, K., Chiang, H. C., Hearn, S. A., Hakker, I., Gatt, A., Shenton, C., Granger, L., Leung, A., Iijima-Ando, K., Zhong, Y. (February 2008) A beta 42 Mutants with Different Aggregation Profiles Induce Distinct Pathologies in Drosophila. PLoS ONE, 3 (2). e1703. ISSN 1932-6203 (Electronic)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18301778
DOI: 10.1371/journal.pone.0001703

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.

Item Type: Paper
Additional Information:
Subjects: diseases & disorders > mental disorders > delirium dementia cognitive disorders > Alzheimer's disease
organism description > animal > insect > Drosophila
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
CSHL Authors:
Communities: CSHL labs > Zhong lab
Watson School > Publications
CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User: CSHL Librarian
Date: 27 February 2008
Date Deposited: 29 Mar 2012 18:31
Last Modified: 01 Dec 2015 21:31
PMCID: PMC2250771
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25589

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