title: Oxidative stress and mitochondria-mediated cell death mechanisms triggered by the familial Danish dementia ADan amyloid.
abstract: Familial Danish Dementia (FDD), an early-onset non-amyloid-β (Aβ) cerebral amyloidosis, is neuropathologically characterized by widespread cerebral amyloid angiopathy, parenchymal amyloid and preamyloid deposits, as well as neurofibrillary degeneration indistinguishable to that seen in Alzheimer's disease (AD). The main amyloid subunit composing FDD lesions, a 34-amino acid de-novo generated peptide ADan, is the direct result of a genetic defect at the 3'-end of the BRI2 gene and the physiologic action of furin-like proteolytic processing at the C-terminal region of the ADan precursor protein. We aimed to study the impact of the FDD mutation, the additional formation of the pyroglutamate (pE) posttranslational modification as well as the relevance of C-terminal truncations -all major components of the heterogeneous FDD deposits- on the structural and neurotoxic properties of the molecule. Our data indicates that whereas the mutation generated a β-sheet-rich hydrophobic ADan subunit of high oligomerization/fibrillization propensity and the pE modification further enhanced these properties, C-terminal truncations had the opposite effect mostly abolishing these features. The potentiation of pro-amyloidogenic properties correlated with the initiation of neuronal cell death mechanisms involving oxidative stress, perturbation of mitochondrial membrane potential, release of mitochondrial cytochrome c, and downstream activation of caspase-mediated apoptotic pathways. The amyloid-induced toxicity was inhibited by targeting specific components of these detrimental cellular pathways, using reactive oxygen scavengers and monoclonal antibodies recognizing the pathological amyloid subunit. Taken together, the data indicate that the FDD mutation and the pE posttranslational modification are both primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule, likely reflecting effect of physiologic clearance mechanisms.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Krysti
authors.initials: K
authors.lastname: Todd
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: jorge.ghiso@nyumc.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: agueda.rostagno@nyumc.org.
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002386:Cataract / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism*; D003638:Deafness / Q000235:genetics / Q000378:metabolism*; D003704:Dementia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D011487:Protein Conformation; D055503:Protein Multimerization; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Apoptosis; Cerebral amyloidosis; Cytochrome c; Familial Danish dementia; Oligomeric amyloid assemblies; Oxidative stress