Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila

Koichi Iijima, HsuehCheng Chinag, Stephen A. Hearn, Inessa Hakker, Anthony Gatt, Christopher Shenton, Linda Granger, Amy Leung, Kanae Iijima-Ando, Yi Zhong

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila braih, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkadly, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42 while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin 5-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.

Original languageEnglish
Article numbere1703
JournalPloS one
Volume3
Issue number2
DOIs
Publication statusPublished - 2008 Feb 27

Fingerprint

Pathology
amyloid
Amyloid
Drosophila
Agglomeration
mutants
protein aggregates
Neurites
neurites
Deposits
Alzheimer disease
Oligomers
Alzheimer Disease
Toxicity
Brain
peptides
Peptides
Mutation
toxicity
Premature Mortality

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Iijima, Koichi ; Chinag, HsuehCheng ; Hearn, Stephen A. ; Hakker, Inessa ; Gatt, Anthony ; Shenton, Christopher ; Granger, Linda ; Leung, Amy ; Iijima-Ando, Kanae ; Zhong, Yi. / Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. In: PloS one. 2008 ; Vol. 3, No. 2.
@article{30e2d8c1b94e48a98a28059c412d5b28,
title = "Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila",
abstract = "Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila braih, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkadly, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42 while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin 5-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.",
author = "Koichi Iijima and HsuehCheng Chinag and Hearn, {Stephen A.} and Inessa Hakker and Anthony Gatt and Christopher Shenton and Linda Granger and Amy Leung and Kanae Iijima-Ando and Yi Zhong",
year = "2008",
month = "2",
day = "27",
doi = "10.1371/journal.pone.0001703",
language = "English",
volume = "3",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

Iijima, K, Chinag, H, Hearn, SA, Hakker, I, Gatt, A, Shenton, C, Granger, L, Leung, A, Iijima-Ando, K & Zhong, Y 2008, 'Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila', PloS one, vol. 3, no. 2, e1703. https://doi.org/10.1371/journal.pone.0001703

Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. / Iijima, Koichi; Chinag, HsuehCheng; Hearn, Stephen A.; Hakker, Inessa; Gatt, Anthony; Shenton, Christopher; Granger, Linda; Leung, Amy; Iijima-Ando, Kanae; Zhong, Yi.

In: PloS one, Vol. 3, No. 2, e1703, 27.02.2008.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila

AU - Iijima, Koichi

AU - Chinag, HsuehCheng

AU - Hearn, Stephen A.

AU - Hakker, Inessa

AU - Gatt, Anthony

AU - Shenton, Christopher

AU - Granger, Linda

AU - Leung, Amy

AU - Iijima-Ando, Kanae

AU - Zhong, Yi

PY - 2008/2/27

Y1 - 2008/2/27

N2 - Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila braih, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkadly, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42 while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin 5-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.

AB - Aggregation of the amyloid-β-42 (Aβ42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Aβ aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Aβ can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Aβ42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Aβ42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Aβ42Arc) and an artificial mutation (Aβ42art) that is known to suppress aggregation and toxicity of Aβ42 in vitro. In the Drosophila braih, Aβ42Arc formed more oligomers and deposits than did wild type Aβ42, while Aβ42art formed fewer oligomers and deposits. The severity of locomotor dysfunction and premature death positively correlated with the aggregation tendencies of Aβ peptides. Surprisingly, however, Aβ42art caused earlier onset of memory defects than Aβ42. More remarkadly, each Aβ induced qualitatively different pathologies. Aβ42Arc caused greater neuron loss than did Aβ42 while Aβ42art flies showed the strongest neurite degeneration. This pattern of degeneration coincides with the distribution of Thioflavin 5-stained Aβ aggregates: Aβ42Arc formed large deposits in the cell body, Aβ42art accumulated preferentially in the neurites, while Aβ42 accumulated in both locations. Our results demonstrate that manipulation of the aggregation propensity of Aβ42 does not simply change the level of toxicity, but can also result in qualitative shifts in the pathology induced in vivo.

UR - http://www.scopus.com/inward/record.url?scp=45949102576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45949102576&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0001703

DO - 10.1371/journal.pone.0001703

M3 - Article

C2 - 18301778

AN - SCOPUS:45949102576

VL - 3

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e1703

ER -