title: Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer's disease.
abstract: Voltage-dependent anion channel (VDAC) is a mitochondrial protein abundantly found in neuronal lipid rafts. In these membrane domains, VDAC is associated with a complex of signaling proteins that trigger neuroprotective responses. Loss of lipid raft integrity may result in disruption of multicomplex association and alteration of signaling responses that may ultimately promote VDAC activation. Some data have demonstrated that VDAC at the neuronal membrane may be involved in the mechanisms of amyloid beta (Aβ)-induced neurotoxicity, through yet unknown mechanisms. Aβ is generated from amyloid precursor protein (APP), and is released to the extracellular space where it may undergo self-aggregation. Aβ aggregate deposition in the form of senile plaques may lead to Alzheimer's disease (AD) neuropathology, although other pathological hallmarks (such as hyper-phosphorylated Tau deposition) also participate in this neurodegenerative process. The present study demonstrates that VDAC1 associates with APP and Aβ in lipid rafts of neurons. Interaction of VDAC1 with APP was observed in lipid rafts from the frontal and entorhinal cortex of human brains affected by AD at early stages (I-IV/0-B of Braak and Braak). Furthermore, Aβ exposure enhanced the dephosphorylation of VDAC1 that correlated with cell death. Both effects were reverted in the presence of tyrosine phosphatase inhibitors. VDAC1 dephosphorylation was corroborated in lipid rafts of AD brains. These results demonstrate that Aβ is involved in alterations of the phosphorylation state of VDAC in neuronal lipid rafts. Modulation of this channel may contribute to the development and progression of AD pathology.
authors.affiliation: Laboratory of Cellular Neurobiology, Department of Physiology, University of La Laguna, School of Medicine, Sta. Cruz de Tenerife, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernandez-Echevarria
authors.affiliation: Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Faculty of Biology, University of La Laguna, Sta. Cruz de Tenerife, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Díaz
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, IDIBELL, CIBERNED, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Laboratory of Cellular Neurobiology, Department of Physiology, University of La Laguna, School of Medicine, Sta. Cruz de Tenerife, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Canerina-Amaro
authors.affiliation: Laboratory of Cellular Neurobiology, Department of Physiology, University of La Laguna, School of Medicine, Sta. Cruz de Tenerife, Spain. Electronic address: rmarin@ull.es.
authors.forename: R
authors.initials: R
authors.lastname: Marin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1
keywords: Alzheimer’s disease; amyloid beta; amyloid precursor protein; lipid rafts; tyrosine phosphatase inhibitor; voltage-dependent anion channel