Cerpa Waldo F, Barría María I, Chacón Marcelo A, Suazo Miriam, González Mauricio, Opazo Carlos, Bush Ashley I, Inestrosa Nibaldo C
Centro FONDAP de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
FASEB J. 2004 Nov;18(14):1701-3. doi: 10.1096/fj.03-1349fje. Epub 2004 Sep 2.
The amyloid precursor protein (APP) contains a Cu binding domain (CuBD) localized between amino acids 135 and 156 (APP135-156), which can reduce Cu2+ to Cu1+ in vitro. The physiological function of this APP domain has not yet being established; nevertheless several studies support the notion that the CuBD of APP is involved in Cu homeostasis. We used APP synthetic peptides to evaluate their protective properties against Cu2+ neurotoxicity in a bilateral intra-hippocampal injection model. We found that human APP135-156 protects against Cu2+-induced neurotoxic effects, such as, impairment of spatial memory, neuronal cell loss, and astrogliosis. APP135-156 lacking two histidine residues showed protection against Cu2+; however, APP135-156 mutated in cysteine 144, a key residue in the reduction of Cu2+ to Cu1+, did not protect against Cu2+ neurotoxicity. In accordance with recent reports, the CuBD of the Caenorhabditis elegans, APL-1, protected against Cu2+ neurotoxicity in vivo. We also found that Cu2+ neurotoxicity is associated with an increase in nitrotyrosine immunofluorescence as well as with a decrease in Cu2+ uptake. The CuBD of APP therefore may play a role in the detoxification of brain Cu.
淀粉样前体蛋白（APP）包含一个位于氨基酸135至156之间（APP135 - 156）的铜结合结构域（CuBD），该结构域在体外可将Cu2+还原为Cu1+。此APP结构域的生理功能尚未明确；然而，多项研究支持APP的CuBD参与铜稳态调节这一观点。我们使用APP合成肽在双侧海马内注射模型中评估其对Cu2+神经毒性的保护特性。我们发现人APP135 - 156可抵御Cu2+诱导的神经毒性作用，如空间记忆受损、神经元细胞丢失和星形胶质细胞增生。缺少两个组氨酸残基的APP135 - 156对Cu2+仍有保护作用；然而，在将Cu2+还原为Cu1+过程中的关键残基半胱氨酸144发生突变的APP135 - 156则无法抵御Cu2+神经毒性。与近期报道一致，秀丽隐杆线虫的APL - 1的CuBD在体内可抵御Cu2+神经毒性。我们还发现Cu2+神经毒性与硝基酪氨酸免疫荧光增加以及Cu2+摄取减少有关。因此，APP的CuBD可能在脑铜解毒中发挥作用。
