Anti-amyloidogenic effect of AA3E2 attenuates beta-amyloid induced toxicity in SK-N-MC cells.
Beta-amyloid peptide (Abeta) is believed to play a recognized role in pathogenesis of Alzheimer's disease (AD). Self-association of Abeta peptide into amyloid fibrils causes neurotoxicity. Compounds capable of interfering with Abeta-Abeta interaction through binding to nucleation sites can inhibit Abeta amyloidogenesis and Abeta-induced cytotoxicity. AA3E2 is a triazine-derivative whose anti-amyloidogenic ability has previously been established. In the present study, we evaluated the protective effect of AA3E3 against Abeta(1-42)-induced toxicity in SK-N-MC cell line. The cell exposure to the co-incubated Abeta(1-42) with AA3E2 decreased the cell viability loss dose-dependently, compared to cells exposed to Abeta(1-42) fibrils. Co-incubation with AA3E2 also attenuated the ROS production, activation of caspase-3 and the extent of apoptotic cell death induced by Abeta(1-42) fibril. Moreover, the 3D structure of the molecular associates between Abeta(1-42) and AA3E2 were theoretically determined by docking studies. Our docking data indicated that AA3E2 inhibits the formation of Abeta fibril likely via binding to the nucleation site within the hydrophobic region of Abeta (KLVFF). These observations provide the background for future design of more elegant beta-breaking agents for dissolution of Abeta fibrillar aggregates.
Shaykhalishahi
Hamed
H
Institute of Biochemistry and Biophysics,University of Tehran, Enghelab Ave., Tehran, Iran.
Taghizadeh
Mohammad
M
Yazdanparast
Razieh
R
Chang
Young-Tae
YT
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; C545493:N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N-butyl-6-decyl-1,3,5-triazine-2,4-diamine; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014227:Triazines; C075222:amyloid beta-protein (1-42); D007770:L-Lactate Dehydrogenase; D053148:Caspase 3