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

Article type: Research Article

Authors: Manczak, Maria^a | Sheiko, Tatiana^b | Craigen, William J.^b | Reddy, P. Hemachandra^{a; *}

Affiliations: [a] Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA | [b] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

Correspondence: [*] Correspondence to: P. Hemachandra Reddy, PhD, Neuroscience Division, Oregon National Primate Research Center, West Campus, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. Tel.: +1 503 629 4045; Fax: +1 503 418 2701; E-mail: [email protected].

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

DOI: 10.3233/JAD-130761

Journal: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 679-690, 2013