Aggregated AA1-42 is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila

The basis for selective vulnerability of certain cell types for misfolded proteins (MP) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MP 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 ringtangle 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 loads 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. That glial cells are viable despite massive loads of Aβ1-42 amyloid implicates that these cells could generate and spread Aβ1-42 fibrils without being harmed.