title: Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons.
abstract: Neurodegeneration associated with Alzheimer's disease is believed to involve toxicity to beta-amyloid (A beta) and related peptides. Treatment of cultured rat hippocampal neurons with A beta 1-40 (1 microM) or the active fragment A beta 25-35 (1 microM) for 5 days led to a approximately 40-50% decrease in neuronal viability. The hydrophilic antioxidant ascorbic acid (300 microM) and the lipophilic antioxidant 2-mercaptoethanol (10 microM) both protected significantly against A beta neurotoxicity. Despite the protective effects of these antioxidants, both acute and chronic treatments with A beta 25-35 did not increase production of superoxide anions, as monitored with the fluorescent probe hydroethidine. Similarly, overexpression of Cu/Zn-superoxide dismutase using adenovirus-mediated gene transfer did not protect against A beta neurotoxicity. A beta neurotoxicity, however, was prevented in cultures infected with a recombinant, replication-defective adenovirus overexpressing the Ca2+ binding protein calbindin D28k. Transforming growth factor-beta 1 (TGF-beta 1) has been shown to protect neurons against both Ca(2+)- and free radical-mediated neuronal degeneration. We found that A beta neurotoxicity was significantly attenuated by single treatments with TGF-beta 1 (0.1-10 ng/ml) and prevented by repetitive treatments (10 ng/ml/day). The protective effects of TGF-beta 1 were associated with a preservation of mitochondrial potential and function, as determined with rhodamine-123-based microfluorimetry. Because both increased oxidative stress and pathophysiological Ca2+ fluxes can impair mitochondrial function, preservation of mitochondrial potential by TGF-beta 1 could be directly associated with its protection against A beta neurotoxicity. The ability of TGF-beta 1 to increase the expression of the anti-apoptotic proteins Bcl-2 and Bcl-XL is discussed in this context.
authors.affiliation: Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Prehn
authors.forename: V P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: J
authors.initials: J
authors.lastname: Jordán
authors.forename: M F
authors.initials: MF
authors.lastname: Galindo
authors.forename: G D
authors.initials: GD
authors.lastname: Ghadge
authors.forename: R P
authors.initials: RP
authors.lastname: Roos
authors.forename: L H
authors.initials: LH
authors.lastname: Boise
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: R J
authors.initials: RJ
authors.lastname: Miller
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000256:Adenoviridae; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D064092:Calbindin 1; D064026:Calbindins; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology*; D008623:Mercaptoethanol / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis / Q000502:physiology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; C576500:Calb1 protein, rat; D064092:Calbindin 1; D064026:Calbindins; D009498:Neurotoxins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D064030:S100 Calcium Binding Protein G; D016212:Transforming Growth Factor beta; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D013779:Tetrodotoxin; D008623:Mercaptoethanol; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D013482:Superoxide Dismutase; D001205:Ascorbic Acid