title: Further evidence on mitochondrial targeting of β-amyloid and specificity of β-amyloid-induced mitotoxicity in neurons.
abstract: OBJECTIVE
  Impaired mitochondrial function has been described in Alzheimer's disease. We previously reported that, in neuronal cells, β-amyloid 1-42 (Aβ(1-42)) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Aβ(1-42) inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Aβ(1-42).
  
  
  RESULTS
  Immunoelectron microscopy revealed that the mitochondrial targeting of Aβ(1-42) was concentration- and time-dependent. Incubation of human neuroblastoma cells with Aβ(1-42) increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Aβ(1-42) targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Aβ(1-42)-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Aβ(1-42) is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Aβ(1-42) was not restricted to brain cells, indicating that it is not cell- or tissue-specific.
  
  
  CONCLUSIONS
  Taken together, these results suggest that extracellular Aβ(1-42) targets neuronal mitochondria to exert its toxic effects.
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Tillement
authors.forename: Laurent
authors.initials: L
authors.lastname: Lecanu
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000502:physiology / Q000506:poisoning*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000502:physiology / Q000506:poisoning*; D016503:Drug Delivery Systems / Q000379:methods*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000502:physiology / Q000506:poisoning*
chemical_list: D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)