Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
J Alzheimers Dis. 2013;37(4):679-90. doi: 10.3233/JAD-130761.
The objective of this study was to elucidate the effect of VDAC1 on Alzheimer's disease (AD)-related genes, mitochondrial activity, and synaptic viability. Recent knockout studies of VDAC1 revealed that homozygote VDAC1 knockout (VDAC1-/-) mice exhibited disrupted learning and synaptic plasticity, and in contrast, VDAC1+/- mice appeared normal in terms of lifespan, fertility, and viability relative to wild-type mice. However, the effects of reduced VDAC1 on mitochondrial/synaptic genes and mitochondrial function in AD-affected neurons are not well understood. In the present study, we characterized mitochondrial/synaptic and AD-related genes and mitochondrial function in VDAC1+/- mice and VDAC1+/+ mice. We found reduced mRNA levels in the AD-related genes, including AβPP, Tau, PS1, PS2, and BACE1; increased levels of the mitochondrial fusion genes Mfn1, Mfn2; reduced levels of the fission genes Drp1 and Fis1; and reduced levels of the mitochondrial permeability transition pore genes VDAC1, ANT, and CypD in VDAC1+/- mice relative to VDAC1+/+ mice. Hexokinase 1 and 2 were significantly upregulated in the VDAC+/- mice. The synaptic genes synaptophysin, synapsin 1 and 2, synaptobrevin 1 and 2, neurogranin, and PSD95 were also upregulated in the VDAC1+/- mice. Free radical production and lipid peroxidation levels were reduced in the VDAC1+/- mice, and cytochrome oxidase activity and ATP levels were elevated, indicating enhanced mitochondrial function in the VDAC1+/- mice. These findings suggest that reduced VDAC1 expression, such as that we found in the VDAC1+/- mice, may be beneficial to synaptic activity, may improve function, and may protect against toxicities of AD-related genes.
本研究旨在阐明 VDAC1 对阿尔茨海默病（AD）相关基因、线粒体活性和突触活力的影响。最近的 VDAC1 基因敲除研究表明，纯合 VDAC1 敲除（VDAC1-/-）小鼠表现出学习和突触可塑性障碍，而 VDAC1+/- 小鼠在寿命、生育力和相对于野生型小鼠的活力方面似乎正常。然而，减少 VDAC1 对 AD 相关神经元中线粒体/突触基因和线粒体功能的影响尚不清楚。在本研究中，我们对 VDAC1+/- 小鼠和 VDAC1+/+ 小鼠的线粒体/突触和 AD 相关基因及线粒体功能进行了特征描述。我们发现 AD 相关基因，包括 AβPP、Tau、PS1、PS2 和 BACE1 的 mRNA 水平降低；线粒体融合基因 Mfn1、Mfn2 的水平升高；分裂基因 Drp1 和 Fis1 的水平降低；以及线粒体通透性转换孔基因 VDAC1、ANT 和 CypD 的水平降低在 VDAC1+/- 小鼠中相对于 VDAC1+/+ 小鼠。己糖激酶 1 和 2 在 VDAC+/- 小鼠中显著上调。突触基因突触小体蛋白、突触素 1 和 2、突触小泡相关蛋白 1 和 2、神经颗粒蛋白和 PSD95 在 VDAC1+/- 小鼠中也上调。VDAC1+/- 小鼠中的自由基产生和脂质过氧化水平降低，细胞色素氧化酶活性和 ATP 水平升高，表明 VDAC1+/- 小鼠中线粒体功能增强。这些发现表明，如我们在 VDAC1+/- 小鼠中发现的那样，减少 VDAC1 的表达可能有利于突触活动，可能改善功能，并可能防止 AD 相关基因的毒性。
