Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans and is characterized by neuronal loss, neurofibrillary tangles and beta-amyloid deposition. The interaction between neurotrophins and their tyrosine kinase (trk) receptors is important for cellular differentiation and survival. Interestingly, marked reductions in neurotrophins and receptors have been reported in AD. The cause of the decrease in these molecules remains unclear. However, the role of beta-amyloid (A beta) appears central in understanding the mechanisms controlling neurotrophin/trk expression. In this study we exposed SHSY5Y neuroblastoma cells to A beta or hydrogen peroxide and measured the expression of trk B/truncated trk B, and brain-derived neurotrophic factor (BDNF)/NT4 at the protein and molecular level. We show that A beta or hydrogen peroxide (H(2)O(2)) induces oxidative stress and cell cytotoxicity. The exposure of cells to A beta results in an increased trk B expression with a concurrent reduction in truncated trk B levels. H(2)O(2) exposure decreased both trk B and truncated trk B levels at the cell surface. At the molecular level trk B RNA increased in the presence of A beta and was unaffected by H(2)O(2). Similarly, BDNF and NT4 levels increased in the presence of A beta. Pre-treatment of cells with the anti-oxidant melatonin returns trk receptor expression, mRNA and BDNF/NT4 secretion to normal levels. These results are significant as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.
Olivieri
G
G
Neuroscience, Novartis, Lichstrasse, 4002 Basel, Switzerland. gianfranco.olivieri@pharma.novartis.com
Otten
U
U
Meier
F
F
Baysang
G
G
Dimitriades-Schmutz
B
B
Müller-Spahn
F
F
Savaskan
E
E
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009447:Neuroblastoma; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D020813:Receptor, trkB; D008550:Melatonin; C073922:neurotrophin 4