Shah Sameer B, Nolan Rhiannon, Davis Emily, Stokin Gorazd B, Niesman Ingrid, Canto Isabel, Glabe Charles, Goldstein Lawrence S B
Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
Neurobiol Dis. 2009 Oct;36(1):11-25. doi: 10.1016/j.nbd.2009.05.016. Epub 2009 Jun 1.
Microtubule-based neuronal transport pathways are impaired during the progression of Alzheimer's disease and other neurodegenerative conditions. However, mechanisms leading to defects in transport remain to be determined. We quantified morphological changes in neuronal cells following treatment with fibrils and unaggregated peptides of beta-amyloid (Abeta). Abeta fibrils induce axonal and dendritic swellings indicative of impaired transport. In contrast, Abeta peptides induce a necrotic phenotype in both neurons and non-neuronal cells. We tested several popular hypotheses by which aggregated Abeta could disrupt transport. Using fluorescent polystyrene beads, we developed experimental models of physical blockage and localized release of reactive oxygen species (ROS) that reliably induce swellings. Like the beads, Abeta fibrils localize in close proximity to swellings; however, fibril internalization is not required for disrupting transport. ROS and membrane permeability are also unlikely to be responsible for fibril-mediated toxicity. Collectively, our results indicate that multiple initiating factors converge upon pathways of defective transport.
在阿尔茨海默病及其他神经退行性疾病进展过程中，基于微管的神经元运输通路会受损。然而，导致运输缺陷的机制仍有待确定。我们对用β-淀粉样蛋白（Aβ）的原纤维和未聚集肽处理后的神经元细胞的形态变化进行了量化。Aβ原纤维会诱导轴突和树突肿胀，这表明运输受损。相比之下，Aβ肽在神经元和非神经元细胞中均诱导坏死表型。我们检验了几种关于聚集的Aβ可能破坏运输的流行假说。使用荧光聚苯乙烯珠，我们建立了物理阻塞和活性氧（ROS）局部释放的实验模型，这些模型能可靠地诱导肿胀。与珠子一样，Aβ原纤维定位于肿胀附近；然而，运输破坏并不需要原纤维内化。ROS和膜通透性也不太可能是原纤维介导毒性的原因。总体而言，我们的结果表明多种起始因素汇聚于有缺陷的运输通路。
