Cheng Irene H, Scearce-Levie Kimberly, Legleiter Justin, Palop Jorge J, Gerstein Hilary, Bien-Ly Nga, Puoliväli Jukka, Lesné Sylvain, Ashe Karen H, Muchowski Paul J, Mucke Lennart
Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
J Biol Chem. 2007 Aug 17;282(33):23818-28. doi: 10.1074/jbc.M701078200. Epub 2007 Jun 4.
Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-beta (Abeta) peptides. In vitro, the "Arctic" mutation (AbetaE22G) accelerated Abeta fibrillization but decreased the abundance of nonfibrillar Abeta assemblies, compared with wild-type Abeta. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to Abeta that increase Abeta production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar Abeta assembly (Abeta56). Mice overexpressing Arctic mutant or wild-type Abeta had similar behavioral and neuronal deficits when they were matched for Abeta56 levels but had vastly different plaque loads. Thus, Abeta*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar Abeta deposits. Therapeutic interventions that reduce Abeta fibrils at the cost of augmenting nonfibrillar Abeta assemblies could be harmful.
许多被怀疑导致神经退行性疾病的蛋白质以多种组装状态存在。对于大多数蛋白质而言，尚不清楚从一种状态转变为另一种状态是有益还是有害。我们利用诱变来改变与阿尔茨海默病（AD）相关的淀粉样β（Aβ）肽的组装状态。在体外，与野生型Aβ相比，“北极”突变（AβE22G）加速了Aβ纤维化，但降低了非纤维状Aβ组装体的丰度。在携带与Aβ相邻且增加Aβ产生的突变的人淀粉样前体蛋白（hAPP）转基因小鼠中，添加北极突变显著增强了神经炎性淀粉样斑块的形成，但降低了一种特定非纤维状Aβ组装体（Aβ56）的相对丰度。当根据Aβ56水平进行匹配时，过表达北极突变体或野生型Aβ的小鼠具有相似的行为和神经元缺陷，但斑块负荷却大不相同。因此，与纤维状Aβ沉积物相比，Aβ*56更有可能是hAPP小鼠功能缺陷的决定因素。以增加非纤维状Aβ组装体为代价来减少Aβ纤维的治疗干预可能是有害的。
