Cell Chemical Biology
Volume 25, Issue 5, 17 May 2018, Pages 595-610.e5
Journal home page for Cell Chemical Biology

Article
Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila

https://doi.org/10.1016/j.chembiol.2018.03.006Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Expressed Aβ1-42 aggregates profoundly in various cell types of Drosophila

  • Aβ1-42 accumulates as extracellular amyloid fibrils when expressed in glial cells

  • Aβ1-42 is highly toxic to neurons in Drosophila

  • Immature intracellular aggregates are more toxic than mature fibrillar Aβ1-42

Summary

The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human Aβ1-42 associated with Alzheimer's disease. Expression of Aβ1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ring-tangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of Aβ1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of Aβ1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that Aβ1-42 cytotoxicity is both cell and aggregate morphotype dependent.

Keywords

Alzheimer's disease
Aβ1-42
Drosophila melanogaster
Gal4/UAS
neurons
glial cells
amyloid polymorphism
cytotoxicity
neurodegeneration

Cited by (0)

5

Lead Contact