Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
PLoS One. 2010 Dec 16;5(12):e15230. doi: 10.1371/journal.pone.0015230.
Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.
脑内淀粉样β肽（Aβ）和氧化应激是阿尔茨海默病（AD）神经元功能障碍和记忆丧失的基础。己糖激酶（HK）是一种关键的糖酵解酶，具有重要的促生存作用，可以减少神经元和其他细胞类型中线粒体活性氧（ROS）的产生并防止细胞凋亡。脑同工酶 HK1 主要与线粒体相关，而 HK 从线粒体释放会导致酶活性显著降低，并引发氧化损伤。我们在此研究了 Aβ 诱导的氧化应激与 HK 活性之间的关系。我们发现 Aβ 触发了 HK1 从线粒体分离，从而降低了皮质神经元中的 HK1 活性。Aβ 低聚物通过降低神经元 ATP 水平进一步损害能量代谢。Aβ 诱导的 HK1 细胞重新分布伴随着过量的 ROS 生成和神经元死亡。2-脱氧葡萄糖阻断了 Aβ 诱导的氧化应激和神经元死亡。结果表明，Aβ 诱导的细胞重新分布和神经元 HK1 的失活在 AD 中的氧化应激和神经退行性变中起重要作用。
