Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease

D C Crowther; K J Kinghorn; E Miranda; R Page; J A Curry; F A I Duthie; D C Gubb; D A Lomas

doi:10.1016/j.neuroscience.2004.12.025

Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease

Neuroscience. 2005;132(1):123-35. doi: 10.1016/j.neuroscience.2004.12.025.

Authors

D C Crowther¹, K J Kinghorn, E Miranda, R Page, J A Curry, F A I Duthie, D C Gubb, D A Lomas

Affiliation

¹ Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK. dcc26@cam.ac.uk

PMID: 15780472
DOI: 10.1016/j.neuroscience.2004.12.025

Abstract

We have developed models of Alzheimer's disease in Drosophila melanogaster by expressing the Abeta peptides that accumulate in human disease. Expression of wild-type and Arctic mutant (Glu22Gly) Abeta(1-42) peptides in Drosophila neural tissue results in intracellular Abeta accumulation followed by non-amyloid aggregates that resemble diffuse plaques. These histological changes are associated with progressive locomotor deficits and vacuolation of the brain and premature death of the flies. The severity of the neurodegeneration is proportional to the propensity of the expressed Abeta peptide to form oligomers. The fly phenotype is rescued by treatment with Congo Red that reduces Abeta aggregation in vitro. Our model demonstrates that intracellular accumulation and non-amyloid aggregates of Abeta are sufficient to cause the neurodegeneration of Alzheimer's disease. Moreover it provides a platform to dissect the pathways of neurodegeneration in Alzheimer's disease and to develop novel therapeutic interventions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology*
Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism*
Animals
Brain / metabolism
Brain / pathology
Brain / physiopathology
Congo Red / pharmacology
Disease Models, Animal
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism*
Inclusion Bodies / genetics
Inclusion Bodies / metabolism
Inclusion Bodies / pathology*
Longevity / genetics
Movement Disorders / genetics
Movement Disorders / metabolism
Movement Disorders / pathology
Nerve Degeneration / genetics
Nerve Degeneration / metabolism
Nerve Degeneration / pathology*
Nervous System / metabolism
Nervous System / pathology*
Nervous System / physiopathology
Neurons / metabolism
Neurons / pathology*
Neuroprotective Agents / pharmacology
Peptide Fragments / genetics
Peptide Fragments / metabolism
Transgenes / genetics
Vacuoles / genetics
Vacuoles / pathology

Substances

Amyloid beta-Peptides
Neuroprotective Agents
Peptide Fragments
amyloid beta-protein (1-42)
Congo Red