Department of Physics, Chemistry and Biology, Linköping University, Linköping SE-581 83, Sweden.
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, 431 80 Mölndal, Sweden.
Cell Chem Biol. 2018 May 17;25(5):595-610.e5. doi: 10.1016/j.chembiol.2018.03.006. Epub 2018 Apr 12.
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.
某些细胞类型对神经退行性疾病中错误折叠蛋白（MPs）的选择性易损性的基础在很大程度上是未知的。了解这种知识对于理解与 CNS 中 MPs 传播有关的疾病进展至关重要。我们通过细胞特异性表达与人 Aβ1-42 相关的果蝇来评估这个问题，该蛋白与阿尔茨海默病有关。Aβ1-42 在各种神经元中的表达导致浓度依赖性的严重神经退行性表型，并且当用聚集物特异性配体分析时，形成具有不成熟纤维特性的神经元内环状缠结样聚集物。出乎意料的是，即使在最强的神经元驱动下，Aβ1-42 从泛神经胶质驱动产生的表达也产生了轻度表型，尽管 Aβ1-42 聚集物的大脑负荷很大。神经胶质细胞形成更成熟的纤维状聚集物，形态上与神经元中发现的聚集物不同，并且主要是细胞外的。我们的研究结果表明，Aβ1-42 的细胞毒性既依赖于细胞又依赖于聚集物形态。
