Molecular Bases of Disease
Expression in Drosophila of Tandem Amyloid β Peptides Provides Insights into Links between Aggregation and Neurotoxicity*

https://doi.org/10.1074/jbc.M112.350124Get rights and content
Under a Creative Commons license
open access

The generation and subsequent aggregation of amyloid β (Aβ) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these peptides have 40 (Aβ40) or 42 residues (Aβ42), the latter having a higher propensity to aggregate in vitro and being the main component of the plaques observed in vivo in AD patients. We have designed a series of tandem dimeric constructs of these Aβ peptides to probe the manner in which changes in the aggregation kinetics of Aβ affect its deposition and toxicity in a Drosophila melanogaster model system. The levels of insoluble aggregates were found to be substantially elevated in flies expressing the tandem constructs of both Aβ40 and Aβ42 compared with the equivalent monomeric peptides, consistent with the higher effective concentration, and hence increased aggregation rate, of the peptides in the tandem repeat. A unique feature of the Aβ42 constructs, however, is the appearance of high levels of soluble oligomeric aggregates and a corresponding dramatic increase in their in vivo toxicity. The toxic nature of the Aβ42 peptide in vivo can therefore be attributed to the higher kinetic stability of the oligomeric intermediate states that it populates relative to those of Aβ40 rather than simply to its higher rate of aggregation.

Alzheimer Disease
Amyloid
Drosophila
Neurodegenerative Diseases
Protein Aggregation

Cited by (0)

Author's Choice—Final version full access.

Alzheimer's Research UK Senior Research Fellow

*

This work was supported by a combined grant from the Medical Research Council and Engineering and Physical Sciences Research Council G0700990.

This article contains supplemental Fig. 1 and Materials and Methods.

1

Both authors are joint first authors.

2

Supported by the Wellcome Trust.

3

Present address: Centre for Genomic Regulation, Universitat Pompeu Fabra, Barcelona, Spain.