A plausible involvement of plasmalemmal voltage‐dependent anion channel 1 in the neurotoxicity of 15‐deoxy‐Δ^12,14‐prostaglandin J₂

Abstract

15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) has been proposed as a mediator of neurodegenerative diseases including Alzheimer's disease (AD) (Yagami et al., 2017, 2018). Pathological features of AD are cortical atrophy, amyloid plaques, neurofibrillary tangles, and neuronal and synaptic loss in the brain including cerebral cortex (Selkoe, 1991). The precursor of 15d-PGJ 2 , prostaglandin D 2 (PGD 2), formation was increased in the frontal cortex of AD patients as compared with those of controls (Iwamoto et al., 1989). Amyloid plaques

Neuronal Protection by Ha-RAS-GTPase Signaling through Selective Downregulation of Plasmalemmal Voltage-Dependent Anion Channel-1

“…Next, we asked if the neuroprotective effect of enhanced RAS signaling could be mimicked by directly inhibiting the pl-VDAC-1 channel in wild-type cortical neurons via the extracellular application of mono-clonal anti-VDAC-1 antibody targeting the N-terminus of VDAC-1 [ 30 , 31 , 32 ]. Therefore, wild-type and synRas primary cortical cultures were preincubated with anti-VDAC-1 one hour before the excitotoxic stimulation with 1.0 mM glutamate for 60 min.…”

“…In addition, anti-VDAC-1 antibody promoted the cellular protection of amyloid β peptide-mediated cell death in the mouse cholinergic septal neuronal cell line SN56 and HT22 cells [ 31 , 61 ], and against 15-deoxy-Δ 12,14 -prostaglandin J2 (15d-PGJ 2 )-mediated cell death in rat primary cortical neurons [ 32 ].…”

“…After excitotoxic stimulation with 0.5 mM glutamate, we observed 40.5 ± 9.5% degenerating wild-type neurons while only 23.3 ± 5.8% synRas-derived neurons showed degeneration resulting in a protection of 57% (Figure 2a). Next, we asked if the neuroprotective effect of enhanced RAS signaling could be mimicked by directly inhibiting the pl-VDAC-1 channel in wild-type cortical neurons via the extracellular application of mono-clonal anti-VDAC-1 antibody targeting the N-terminus of VDAC-1 [30][31][32]. Therefore, wild-type and synRas primary cortical cultures were preincubated with anti-VDAC-1 one hour before the excitotoxic stimulation with 1.0 mM glutamate for 60 min.…”

“…Interestingly, not only mt-VDAC-1 but also pl-VDAC-1 participates in apoptosis. Under apoptotic conditions, pl-VDAC-1 becomes activated, and the channel opens, whereas its blockage, e.g., due to the extra-cellular application of anti-VDAC-1 antibodies, prevents apoptosis [ 30 , 31 , 32 ]. In post mortem brains of Alzheimer’s disease patients, VDAC-1 is overexpressed [ 33 ], and therefore, prodromal Alzheimer’s disease might be recognized by VDAC-1 overexpression as a biomarker [ 34 ].…”