Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila. Issue 5 (17th May 2018)

• Record Type: Journal Article
• Authors: Jonson, Maria; Nyström, Sofie; Sandberg, Alexander; Carlback, Marcus; Michno, Wojciech; Hanrieder, Jörg; Starkenberg, Annika; Nilsson, K. Peter R.; Thor, Stefan; Hammarström, Per
• Is Part Of: Cell chemical biology. Volume 25:Issue 5(2018)
• Page Start: 595
• Page End: 610.e5
• Publication Date: 2018-05-17
• Subjects: Alzheimer's disease -- Aβ1-42 -- Drosophila melanogaster -- Gal4/UAS -- neurons -- glial cells -- amyloid polymorphism -- cytotoxicity -- neurodegeneration; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.03.006
• Languages: English
• ISSNs: 2451-9456

Abstract

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. Graphical Abstract: 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 Abstract : Jonson et al. used transgenic Drosophila to understand cell-specific response to protein aggregates in neurodegenerative disease. They demonstrate that the Alzheimer-associated peptide Aβ1-42 form various amyloid structures with different toxic properties when expressed in different cell types of the brain.