title: Interaction of Aβ(25-35) fibrillation products with mitochondria: Effect of small-molecule natural products.
abstract: The 25-35 fragment of the amyloid β (Aβ) peptide is a naturally occurring proteolytic by-product that retains the pathophysiology of its larger parent molecule, whose deposition has been shown to involve mitochondrial dysfunction. Hence, disruption of Aβ(25-35) aggregates could afford an effective remedial strategy for Alzheimer's disease (AD). In the present study, the effect of a number of selected small-molecule natural products (polyphenols: resveratrol, quercetin, biochanin A, and indoles: indole-3-acetic acid, indole-3-carbinol (I3C)) on Aβ(25-35) fibrillogenesis was explored under physiological conditions, and interaction of the resulting structures with rat brain mitochondria was investigated. Several techniques, including fluorescence, circular dichroism, and transmission electron microscopy were utilized to characterize the aggregation products, and possible mitochondrial membrane permeabilization was determined following release of marker enzymes. Results demonstrate the capacity of Aβ(25-35) fibrils to damage mitochondria and suggest how small molecules may afford protection. While I3C appeared more effective in inhibiting the fibrillation process, all natural products behaved similarly in destabilizing preformed aggregates. It is concluded that elucidation of such protection may provide important insights into the development of preventive and therapeutic agents for AD.
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghobeh
authors.forename: Shahin
authors.initials: S
authors.lastname: Ahmadian
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Meratan
authors.forename: Azadeh
authors.initials: A
authors.lastname: Ebrahim-Habibi
authors.forename: Atiyeh
authors.initials: A
authors.lastname: Ghasemi
authors.forename: Mahshid
authors.initials: M
authors.lastname: Shafizadeh
authors.forename: Mohsen
authors.initials: M
authors.lastname: Nemat-Gorgani
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D001688:Biological Products; D010446:Peptide Fragments; D054852:Small Molecule Libraries; C074636:amyloid beta-protein (25-35)
keywords: Amyloid beta(25-35) fibrillogenesis; indoles; mitochondrial membrane permeabilization; natural-product inhibitors; polyphenols