Abstract

Alzheimer's disease (AD) is associated with a reduction in cholinergic activity as a result of specific neuronal loss. Current potential treatments for the disease include both cholinomimetic drugs and anticholinesterase inhibitors. One of the drugs approved by the FDA is tacrine (9-amine-1,2,3,4 tetrahydroacridine; THA), a strong acetylcholinesterase (AChE) inhibitor, We have studied the effects of tacrine on glial and neuronal cells in culture assessing cell survival and viability and morphology, Lactate dehydrogenase (LDH) activity and methylthiazol-diphenyltetrazolium (MTT) reduction were used as toxicity indicators. We found that tacrine toxicity on rat B12 glial cells and mouse Neuro 2A cells was strongly dependent on its concentration (up to 500 mu M) and time of exposure. The toxic effect was not prevented by serum factors nor by bovine serum albumin, Fluorescein-conjugated phalloidin was used to examine the arrangement of actin filaments at substrate adhesion regions and cell-cell contacts. Primary events following exposure to tacrine included changes in cell morphology, disappearance of actin filament bundles, and disruption of focal adhesion contacts. At concentrations between 10 and 50 mu M, tacrine induced neurite outgrowth in Neuro 2A cells, an effect that was not observed in B12 cells, suggesting that certain tacrine effects could be specific for neuronal cells, Although similar trends of response were observed for both cell types, some differences between undifferentiated and differentiated cells were apparent. (C) 1998 Wiley-Liss, Inc.