TRANSFORMING-GROWTH-FACTOR BETA-2 CAN EXERT PROTECTION TOWARDS AND EXACERBATION OF BETA-AMYLOID TOXICITY DEPENDING UPON GROWTH-FACTOR CONCENTRATION AND LENGTH OF EXPOSURE

Alzheimer's disease (AD) is characterized by the extracellular accumul ation of beta-amyloid (beta A), and the intracellular accumulation of paired helical filaments (PHFs) comprised of hyperphosphorylated forms of the microtubule-associated protein tau. Treatment of cultured neur onal cells with beta A induces the accumulation of hyperphosphorylated tau. Since exogenous growth factors represent potential therapeutic a gents for AD neurodegeneration, we treated SH-SY-5Y human neuroblastom a cells with transforming growth factor beta 2 (TGF-beta 2) prior to a nd simultaneously with beta A. Treatment with 22 mu M beta A(25-35) in creased immunoreactivity with a monoclonal antibody (PHF-1) that react s with PHFs. Pre-treatment with 5-50ng/ml TGF-beta 2 for 24hr diminish ed beta A-induced PHF-1 accumulation provided TGF-beta 2 was maintaine d during beta A treatment. Withdrawal of TGF-beta 2 at the onset of be ta A treatment or simultaneous treatment with TGF-beta 2 and beta A di d not induce similar protection. When cells were pretreated for 24hr w ith TGF-beta 2, and the remaining TGF-beta 2 was diluted by half simul taneously with beta A treatment, TGF-beta 2 exacerbated the extent of PHF-I induced by beta A. These findings indicate that, depending upon the nature of treatment, growth factors can induce both protective and exacerbatory influences on the extent of neurodegeneration.