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 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.
Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
Maria
M
Manczak
Tatiana
T
Sheiko
William J
WJ
Craigen
P Hemachandra
PH
Reddy
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D015536:Down-Regulation; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D050995:Voltage-Dependent Anion Channel 1 / Q000037:antagonists & inhibitors / Q000172:deficiency*
C494763:Vdac1 protein, mouse; D050995:Voltage-Dependent Anion Channel 1
Amyloid-β; knockout mouse model; mitochondrial function; oxidative stress; real-time reverse transcriptase PCR; voltage-dependent anion channel 1