PROTECTIVE EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON BETA-AMYLOID NEUROTOXICITY IN RAT HIPPOCAMPAL-NEURONS

Neurodegeneration associated with Alzheimer's disease is believed to i nvolve toxicity to beta-amyloid (A beta) and related peptides. Treatme nt of cultured rat hippocampal neurons with A beta 1-40 (1 mu M) Or th e active fragment A beta 25-35 (1 mu M) for 5 days led to a similar to 40-50% decrease in neuronal viability. The hydrophilic antioxidant as corbic acid (300 mu M) and the lipophilic antioxidant 2-mercaptoethano l (10 mu M) 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 su peroxide anions, as monitored with the fluorescent probe hydroethidine . Similarly, overexpression of Cu/Zn-superoxide dismutase using adenov irus-mediated gene transfer did not protect against A beta neurotoxici ty. A beta neurotoxicity, however, was prevented in cultures infected with a recombinant, replication-defective adenovirus overexpressing th e Ca2+ binding protein calbindin D-28k. Transforming growth factor-bet a 1 (TGF-beta 1) has been shown to protect neurons against both Ca2+- and free radical-mediated neuronal degeneration. We found that A beta neurotoxicity was significantly attenuated by single treatments with T GF-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 wi th rhodamine-123-based microfluorimetry. Because both increased oxidat ive 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 neurotoxici ty. The ability of TGF-beta 1 to increase the expression of the anti-a poptotic proteins Bcl-2 and Bcl-x(L) is discussed in this context.