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Fig. 1 | Translational Neurodegeneration

Fig. 1

From: Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Fig. 1

Aβ induces VDAC1 overexpression, oligomerization, and apoptotic cell death in primary neural cultures. Primary neural cultures were infected with App swe/lnd-EGFP Sindbis virus for 16 h (Additional file 1: Fig. S1g) to overexpress and secrete Aβ into the medium (conditioned medium, Cond. Med.). a Cells were incubated with and without 50% conditioned medium for 6, 24, and 48 h and IF stained for VDAC1. b Quantification of VDAC1 IF staining. c, d IF staining for VDAC1 of cells incubated for 48 h with 50% conditioned medium in the presence and absence of VBIT-4 (10 μM), and its quantification. ef Cultured neurons incubated with and without 50% conditioned medium for 24 h were co-immunostained for VDAC1 and p53 (e) and their expression levels were quantified (f). g Primary neural cultures were infected with App swe/lnd-EGFP Sindbis virus for 20 h (Inf.), then conditioned medium (Cond. Med.) was collected, and control neuronal culture was incubated with and without 50% conditioned medium for 48 h and subjected to immunoblotting for VDAC1 and p53. The p53 and monomeric VDAC1 levels are shown in the bottom in relative units (RU). The low exposure (Low Exp.) is presented to show the increase in monomeric VDAC1 levels. The positions of VDAC1 monomers and oligomers and of the molecular weight standards are indicated. h VDAC1 promoter sites that match the sequence profiles generated from Aβ ID decamers [54]. The distance from the VDAC1 transcription start site and the q-value of a motif occurrence are presented. i Immunostaining for activated caspase-3 and VDAC1, in control and conditioned medium treated culture. Quantification of activated caspase-3 levels are shown in (f). j Proposed coupling of VDAC1 overexpression induced by apoptosis stimuli or Aβ and VDAC1 oligomerization forming a large channel, with and without Aβ participation, mediating the release of apoptogenic protein cytochrome c (Cyto c) and apoptosis-inducing factor (AIF) from the intermembrane space (IMS). The VDAC1-interacting molecule, VBIT-4, prevents VDAC1 oligomerization and apoptosis. The functions of VDAC1 in cell life include (blue arrows): control of metabolic cross-talk between the mitochondria and the rest of the cell; transport of Ca2+ to and from the IMS; mediation of cellular energy production by transporting ATP/ADP and NAD +/NADH and fatty acid transport as acyl-CoA (FA-CoA) form, and regulation of glycolysis via binding of hexokinase (HK). The TCA cycle, the electron transport chain (ETC), and the ATP synthase (F0F1) are also presented

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