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

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

Maria Manczak  1 , Tatiana Sheiko, William J Craigen, P Hemachandra Reddy
Affiliations

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

Maria Manczak et al. J Alzheimers Dis. 2013.

Abstract

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.

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

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Figures

Figure 1
Figure 1
Immunoblotting analysis of mitochondrial permeability transition pore proteins in VDAC1+/+ mice (n=4) and VDAC1+/− (n=4) mice.
Figure 2
Figure 2
Mitochondrial functional parameters in VDAC1+/+mice (n=4) and VDAC+/− mice (n=4). A represents hydrogen peroxide production, significantly decreased in VDAC1+/− mice relative to VDAC+/+ mice. B. Represents lipid peroxidation levels, significantly decreased in VDAC1+/− mice relative to VDAC+/+ mice. C. Represents cytochrome c oxidase activity, significantly increased in VDAC1+/− mice relative to VDAC+/+ mice. D. Represents ATP levels, significantly increased in VDAC1+/− mice relative to VDAC+/+ mice.
Figure 3
Figure 3
GTPase Drp1 activity in VDAC1+/+ (n=4) and VDAC+/− mice (n=4). Significantly decreased reduced in VDAC1+/− mice relative to VDAC+/+ mice.
See this image and copyright information in PMC

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