Reduced VDAC1 Protects Against Alzheimer's Disease, Mitochondria, and Synaptic Deficiencies

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 A beta PP, 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.