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Updated: Jun 27, 2026
Mass Histology to Quantify Neurodegeneration in Drosophila
Published on: December 15, 2016
Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function
Katia Carmine-Simmen1, Thomas Proctor, Jakob Tschäpe
1Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Abstract:
The accumulation of amyloid-beta (Abeta) into plaques is a hallmark feature of Alzheimer's disease (AD). While amyloid precursor protein (APP)-related proteins are found in most organisms, only Abeta fragments from human APP have been shown to induce amyloid deposits and progressive neurodegeneration. Therefore, it was suggested that neurotoxic effects are a specific property of human Abeta. Here we show that Abeta fragments derived from the Drosophila orthologue APPL aggregate into intracellular fibrils, amyloid deposits, and cause age-dependent behavioral deficits and neurodegeneration. We also show that APPL can be cleaved by a novel fly beta-secretase-like enzyme. This suggests that Abeta-induced neurotoxicity is a conserved function of APP proteins whereby the lack of conservation in the primary sequence indicates that secondary structural aspects determine their pathogenesis. In addition, we found that the behavioral phenotypes precede extracellular amyloid deposit formation, supporting results that intracellular Abeta plays a key role in AD.
Insights
Alzheimer's disease (AD) amyloid-beta (Abeta) neurotoxicity is conserved across species. Fruit fly Abeta fragments form fibrils and cause neurodegeneration, suggesting conserved pathogenesis mechanisms in APP proteins.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyloid-beta (Abeta) plaque accumulation is a hallmark of Alzheimer's disease (AD).
- Previous research suggested Abeta neurotoxicity was specific to human amyloid precursor protein (APP).
Purpose of the Study:
- To investigate if Abeta fragments from non-human organisms can induce neurotoxicity and amyloid deposits.
- To explore the conserved mechanisms of APP protein function and neurodegeneration.
Main Methods:
- Generated and analyzed Abeta fragments from the Drosophila orthologue of APP (APPL).
- Assessed fibril formation, amyloid deposit induction, and neurodegenerative effects in Drosophila.
- Identified a novel fly beta-secretase-like enzyme involved in APPL cleavage.
Main Results:
- Drosophila APPL-derived Abeta fragments aggregate into intracellular fibrils and amyloid deposits.
- These fragments cause age-dependent behavioral deficits and neurodegeneration in flies.
- Behavioral changes preceded extracellular amyloid deposit formation, highlighting intracellular Abeta's role.
Conclusions:
- Abeta-induced neurotoxicity is a conserved function of APP proteins, not limited to humans.
- Secondary structural aspects, rather than primary sequence, may determine Abeta pathogenesis.
- Intracellular Abeta plays a critical role in AD pathogenesis, preceding extracellular plaque formation.
