Nordberg_2000_Neurotox.Res_2_157

Alzheimer's disease is the most common dementia disorder characterized by multiple pathological changes in the brain leading to a progressive memory loss and other cognitive symptoms producing occupational and social disabilities. Although a great deal of progress has been made in recent years in further understanding the genetic aberrations and patho-physiological processes of Alzheimer's disease there is still no cure of the disease. The transmitter replacement therapy is so far the most explored therapy. Three cholinesterase inhibitors have so far been approved and presently in clinical use in many countries. Although the cholinesterase inhibitors generally appear to produce symptomatic effects with palliative effect on existing cognitive disturbances recent data suggest that they also may have effect on progression of the disease including possible neuroprotective effects. Possible interactions between Abeta and cholinergic neurotransmission may exist. Treatment of cells with Abeta causes decreased cholinergic activity. Pretreatment of PC12 cells with cholinesterase inhibitors such as tacrine and donepezil in clinical relevant concentrations can attenuate Abeta (25-35) toxicity through mechanisms which may be mediated via nicotinic receptors. Estrogen has been shown to protect against Abeta toxicity in different cell lines and also to reduce the formation of Abeta. Its mechanism for the neuroprotective effect is however not fully clarified. A potentiation of the clinical effect of cholinesterase inhibitors in Alzheimer patients has been given together with estrogen. Experimental data suggest that the neuroprotective effect of estrogen as studied in PC12 cells was mediated at least partly via the alpha(7) nicotinic receptor. Treatment with Abeta in nanomolar concentrations for 7 days in PC12 cells significantly decreased the number of nicotinic receptor binding sites and mRNA levels. The effects by Abeta on nicotinic receptors are prevented by nicotine pretreatment. The finding suggests a possible link between Abeta and nicotinic receptor deficits in Alzheimer patients in the early course of the disease.