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

Maria Manczak, Tatiana Sheiko, William J. Craigen, P. Hemachandra Reddy

    Research output: Contribution to journalArticle

    33 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)679-690
    Number of pages12
    JournalJournal of Alzheimer's Disease
    Volume37
    Issue number4
    DOIs
    StatePublished - 2013

    Keywords

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

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Clinical Psychology
    • Geriatrics and Gerontology
    • Psychiatry and Mental health

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