Over the past several years, the toxic mechanism of proliferating misfolded proteins (MPs) as initiators and drivers of neurodegeneration has gained momentum. Nonetheless, the notion of selective vulnerability of specific cell types in neurodegenerative diseases (NDs) is largely uncharted territory. NDs show vast variations in disease onset and clinical phenotype depending on culprit MP and cell type involved. Many researchers in the field aim to target MP spreading to mitigate neurodegeneration. But there are outstanding questions:

How can NDs stay dormant for decades before presenting clinical symptoms?How can certain patients carry large loads of MPs without showing symptoms? 

Amyloid fibrils and oligomers are structurally heterogeneous showing conformational and ultrastructural polymorphism. This poses a challenge both for diagnostics and for therapeutic interventions. This polymorphism likely contributes to variable disease progression because protein structure determines function. Furthermore, various cell types show different sensitivity towards distinct MPs and fibril polymorphs. Unravelling how CNS support cells, glia, versus neurons handle MPs, especially Aβ amyloid linked to Alzheimer’s disease has been hampered by the fact that transgenic (tg) mice (overproducing human Aβ) show very little neurodegeneration. The situation is dramatically different in tg-Drosophila. Here, Aβ1–42 is a potent neurotoxin and is therefore arguably a more suitable model animal for such studies [1]. We addressed the question if cell toxicity is cell type and amyloid polymorph dependent.