The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid  (A). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in A cell penetration and cell death induction. A directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated A interacted with bilayer-reconstituted VDAC1 and increased its conductance ϳ2-fold. Incubation of cells with A resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented A cellular entry and A-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented A entry into the cytosol as well as A-induced toxicity. Finally, the mode of A-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that A-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting A cytotoxicity is thus a potential new therapeutic strategy for AD treatment.
Alzheimer disease (AD)3 pathology is characterized by cognitive decline, brain synaptic dysfunction, inflammatory responses, and mitochondrial dysfunction (1). The aggregation of the amyloid  peptide (A) is proposed to play a key role in AD pathogenesis (2). A is the post-proteolytic product of sequential cleavages of amyloid precursor protein by -secretase and ␥-secretase. The commonly used 42-amino acid-long A (A42) self-aggregates into oligomers, with larger aggregates forming A plaques. However, soluble A oligomers were proposed to be the cytotoxic form of the protein, acting extraor/and intracellularly (3).The severity of dementia and brain hypometabolism has been previously shown to be tightly linked (4), with brain hypometabolism preceding clinical signs of AD. This is directly associated with mitochondrial dysfunction being an early event in AD pathogenesis, as reflected in reduced metabolism, disruption of Ca 2ϩ homeostasis, increased free radical production, and lipid peroxidation (5-9). A also affects mitochondrial respiration (10) and activates cytochrome c release, resulting in apoptosis (11). Importantly, A does not cause toxicity in cells depleted of mitochondria (12). Finally, the mitochondrial protein, the voltage-dependent anion channel (VDAC), was shown to participate...
