Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Hum Mol Genet. 2012 Dec 1;21(23):5131-46. doi: 10.1093/hmg/dds360. Epub 2012 Aug 27.
The purpose of our study was to determine the relationship between voltage-dependent anion channel 1 protein (VDAC1) and amyloid beta (Aβ) and phosphorylated tau in Alzheimer's disease (AD). Using brain specimens from AD patients, control subjects and 6-, 12- and 24-month-old Aβ precursor protein (APP) transgenic mice, we studied VDAC1 protein levels. Further, we also studied the interaction between VDAC1 and Aβ (monomers and oligomers) and phosphorylated tau, using cortical issues from AD patients, control subjects, APP, APP/PS1 and 3XTg.AD mice. We also studied age- and VDAC1-linked, mutant APP/Aβ-induced mitochondrial dysfunction in APP and non-transgenic wild-type (WT) mice. We found progressively increased levels of VDAC1 in the cortical tissues from the brains of patients with AD, relative to control subjects, and significantly increased levels of VDAC1 in the cerebral cortices of 6-, 12- and 24-month-old APP transgenic mice, relative to the age-matched control WT mice. Interestingly, we found VDAC1 interacted with Aβ and phosphorylated tau in the brains from AD patients and from APP, APP/PS1 and 3XTg.AD mice. We found progressively increased mitochondrial dysfunction in APP mice relative to WT mice. These observations led us to conclude that VDAC1 interacts with Aβ, and phosphorylated tau may in turn block mitochondrial pores, leading to mitochondrial dysfunction in AD pathogenesis. Based on current study observations, we propose that reduced levels of VDAC1, Aβ and phosphorylated tau may reduce the abnormal interaction between VDAC1 and APP, VDAC1 and Aβ, and VDAC1 and phosphorylated tau; and that reduced levels of VDAC1, Aβ and phosphorylated tau may maintain normal mitochondrial pore opening and pore closure, ultimately leading to normal mitochondrial function, mitochondria supplying ATP to nerve terminals and boosting synaptic and cognitive function in AD.
我们的研究目的是确定电压依赖性阴离子通道 1 蛋白 (VDAC1) 与淀粉样β (Aβ) 和磷酸化 tau 在阿尔茨海默病 (AD) 中的关系。我们使用 AD 患者、对照受试者和 6、12 和 24 个月大的 APP 转基因小鼠的脑标本研究了 VDAC1 蛋白水平。此外，我们还研究了 VDAC1 与 Aβ（单体和寡聚体）和磷酸化 tau 之间的相互作用，使用 AD 患者、对照受试者、APP、APP/PS1 和 3XTg.AD 小鼠的皮质组织。我们还研究了与年龄和 VDAC1 相关的、突变 APP/Aβ 诱导的 APP 和非转基因野生型 (WT) 小鼠中的线粒体功能障碍。我们发现 AD 患者大脑皮质组织中 VDAC1 的水平逐渐升高，与对照受试者相比，6、12 和 24 个月大的 APP 转基因小鼠大脑皮质中 VDAC1 的水平显著升高，与年龄匹配的 WT 小鼠相比。有趣的是，我们发现 VDAC1 与 AD 患者和 APP、APP/PS1 和 3XTg.AD 小鼠大脑中的 Aβ 和磷酸化 tau 相互作用。我们发现 APP 小鼠相对于 WT 小鼠的线粒体功能障碍逐渐增加。这些观察结果使我们得出结论，VDAC1 与 Aβ相互作用，磷酸化 tau 可能反过来阻止线粒体孔，导致 AD 发病机制中的线粒体功能障碍。基于目前的研究观察结果，我们提出，VDAC1、Aβ 和磷酸化 tau 水平降低可能会减少 VDAC1 与 APP、VDAC1 与 Aβ 和 VDAC1 与磷酸化 tau 之间的异常相互作用；并且 VDAC1、Aβ 和磷酸化 tau 水平降低可能会维持正常的线粒体孔开放和孔关闭，最终导致正常的线粒体功能，为神经末梢提供 ATP，增强 AD 中的突触和认知功能。
