Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer's disease mouse model.
Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer's disease mouse model.
复制标题
DOI：
10.1089/neu.2013.3017
复制
发表时间：
2014
影响因子：
4.2
通讯作者：
Patricia M. Washington;Nicholas Morffy;Maia Parsadanian;David N Zapple;Mark P. Burns
中科院分区：
文献类型：
--
作者：
Patricia M. Washington;Nicholas Morffy;Maia Parsadanian;David N Zapple;Mark P. Burns
可溶性淀粉样蛋白-β（Aβ）寡聚体被假设为阿尔茨海默病（AD）的致病物质，创伤性脑损伤（TBI）后大脑中寡聚体水平的增加可能会加剧继发性损伤途径，并导致晚年AD风险增加。为了确定TBI是否会导致Aβ在脑内聚集和寡聚化，我们将三重转基因AD模型小鼠暴露于受控的皮质撞击损伤，并在损伤后1、3和7天通过酶联免疫吸附测定（ELISA）测量可溶性、不溶性和寡聚Aβ的水平。脑损伤后1d，脑皮质可溶性和不溶性Aβ40和Aβ42水平均明显升高。我们证实了先前的研究结果，即通过免疫组织化学和生物化学鉴定受损轴突是Aβ积聚的主要部位。我们还报道了可溶性Aβ寡聚体在损伤的皮质中显著增加，如ELISA和Western blot所示。有趣的是，小鼠大脑能够快速清除创伤诱导的Aβ，可溶性和不溶性Aβ物质在损伤后7天恢复到假手术水平。总之，我们证明了TBI导致Aβ在脑中的急性蓄积和聚集，包括低分子量和高分子量Aβ寡聚体的形成。损伤后急性Aβ形成和聚集为毒性物质可能在创伤后继发性损伤级联中发挥作用，并且长期可能导致日后发生AD的风险增加。
Soluble amyloid-beta (Aβ) oligomers are hypothesized to be the pathogenic species in Alzheimer's disease (AD), and increased levels of oligomers in the brain subsequent to traumatic brain injury (TBI) may exacerbate secondary injury pathways and underlie increased risk of developing AD in later life. To determine whether TBI causes Aβ aggregation and oligomerization in the brain, we exposed triple transgenic AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble, and oligomeric Aβ by enzyme-linked immunosorbent assay (ELISA) at 1, 3, and 7 days postinjury. TBI rapidly increased levels of both soluble and insoluble Aβ40 and Aβ42 in the injured cortex at 1 day postinjury. We confirmed previous findings that identified damaged axons as a major site of Aβ accumulation using both immunohistochemistry and biochemistry. We also report that soluble Aβ oligomers were significantly increased in the injured cortex, as demonstrated by both ELISA and Western blot. Interestingly, the mouse brain is able to rapidly clear trauma-induced Aβ, with both soluble and insoluble Aβ species returning to sham levels by 7 days postinjury. In conclusion, we demonstrate that TBI causes acute accumulation and aggregation of Aβ in the brain, including the formation of low- and high-molecular-weight Aβ oligomers. The formation and aggregation of Aβ into toxic species acutely after injury may play a role in secondary injury cascades after trauma and, chronically, may contribute to increased risk of developing AD in later life.