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J Alzheimers Dis. 2013;37(4):679-90. doi: 10.3233/JAD-130761.

Reduced VDAC1 protects against Alzheimer's disease, mitochondria, and synaptic deficiencies.

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  • 1Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.


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.


Amyloid-β; knockout mouse model; mitochondrial function; oxidative stress; real-time reverse transcriptase PCR; voltage-dependent anion channel 1

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