George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA.
Metallomics. 2020 Apr 1;12(4):539-546. doi: 10.1039/c9mt00306a. Epub 2020 Feb 27.
Accumulation of fibrillar amyloid β-protein (Aβ) in parenchymal plaques and in blood vessels of the brain, the latter condition known as cerebral amyloid angiopathy (CAA), are hallmark pathologies of Alzheimer's disease (AD) and related disorders. Cerebral amyloid deposits have been reported to accumulate various metals, most notably copper and zinc. Here we show that, in human AD, copper is preferentially accumulated in amyloid-containing brain blood vessels compared to parenchymal amyloid plaques. In light of this observation, we evaluated the effects of reducing copper levels in Tg2576 mice, a transgenic model of AD amyloid pathologies. The copper chelator, tetrathiomolybdate (TTM), was administered to twelve month old Tg2576 mice for a period of five months. Copper chelation treatment significantly reduced both CAA and parenchymal plaque load in Tg2576 mice. Further, copper chelation reduced parenchymal plaque copper content but had no effect on CAA copper levels in this model. These findings indicate that copper is associated with both CAA deposits and parenchymal amyloid plaques in humans, but less in Tg2576 mice. TTM only reduces copper levels in plaques in Tg2576 mice. Reducing copper levels in the brain may beneficially lower amyloid pathologies associated with AD.
纤维状淀粉样 β 蛋白 (Aβ) 在脑实质斑块和血管中的积累，后者被称为脑淀粉样血管病 (CAA)，是阿尔茨海默病 (AD) 和相关疾病的标志性病理学特征。已有报道称，脑淀粉样沉积物中积累了各种金属，最显著的是铜和锌。在这里，我们表明，在人类 AD 中，与实质淀粉样斑块相比，铜优先在含有淀粉样蛋白的脑血管中积累。鉴于这一观察结果，我们评估了降低 Tg2576 小鼠（一种 AD 淀粉样病理的转基因模型）中铜水平的效果。铜螯合剂四硫钼酸盐 (TTM) 被施用于 12 个月大的 Tg2576 小鼠，为期五个月。铜螯合治疗显著降低了 Tg2576 小鼠的 CAA 和实质斑块负荷。此外，铜螯合治疗降低了实质斑块中的铜含量，但对该模型中的 CAA 铜水平没有影响。这些发现表明，铜与人类的 CAA 沉积物和实质淀粉样斑块都有关，但在 Tg2576 小鼠中较少。TTM 仅降低 Tg2576 小鼠斑块中的铜水平。降低大脑中的铜含量可能有益于降低与 AD 相关的淀粉样病理学。
