title: The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy.
abstract: 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 β (Aβ). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼ 2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented Aβ entry into the cytosol as well as Aβ-induced toxicity. Finally, the mode of Aβ-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 Aβ-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting Aβ cytotoxicity is thus a potential new therapeutic strategy for AD treatment.
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel and.
authors.forename: Angela
authors.initials: A
authors.lastname: Smilansky
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel and.
authors.forename: Liron
authors.initials: L
authors.lastname: Dangoor
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel and.
authors.forename: Itay
authors.initials: I
authors.lastname: Nakdimon
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel and.
authors.forename: Danya
authors.initials: D
authors.lastname: Ben-Hail
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853.
authors.forename: Dario
authors.initials: D
authors.lastname: Mizrachi
authors.affiliation: From the Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel and vardasb@bgu.ac.il.
authors.forename: Varda
authors.initials: V
authors.lastname: Shoshan-Barmatz
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C494762:VDAC1 protein, human; D045304:Cytochromes c; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase
keywords: Alzheimer disease; amyloid-beta (AB); apoptosis; mitochondria; peptides; siRNA; small interfering RNA (siRNA); voltage-dependent anion channel (VDAC)