Aggregated Aβ1-42 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 (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. 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. © 2018 Elsevier Ltd

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Alzheimer's disease

amyloid polymorphism

Aβ1-42

cytotoxicity

Drosophila melanogaster

Gal4/UAS

glial cells

neurodegeneration

neurons

amyloid

amyloid beta protein[1-42]

green fluorescent protein

protein aggregate

animal experiment

animal tissue

Article

controlled study

Drosophila

glia cell

locomotion

motoneuron

nonhuman

phenotype

priority journal

protein aggregation

protein conformation

protein expression

retina

Alzheimer's disease

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