Muscarinic receptor subtype determines vulnerability to amyloid beta toxicity in transfected cos-7 cells.

Abstract

Research has suggested that there are age-related increases in neuronal sensitivity to insult from oxidative stress (OS) and that the CNS alterations seen in Alzheimer disease (AD) and vascular dementia (VaD) are superimposed upon declining nervous and vascular systems. Since muscarinic receptors (mAChR) may be important in regional sensitivity, regulation of micro- circulation, and in various aspects of both neuronal (AbetaPP processing) and vascular functioning, we postulated that the various mAChR subtypes may show differential sensitivity to OS. Indeed, recent findings indicated that M1, M2, or M4 AChR-transfected COS-7 cells showed greater OS sensitivity [as reflected in Ca2+ buffering (i.e., the ability to extrude or sequester Ca2+ following oxotremorine-induced depolarization)] than those transfected with M3 or M5 AChR when exposed to dopamine. Interestingly, the results from the present study indicate that similar findings were also observed when the cells were exposed to Abeta 25-35 and Abeta 1-40 showed similar effects on M1 and M3 AChR. No effects were seen with Abeta 35-25 or Abeta 40-1. Thus, cells transfected with M1, M2 or M4 AChR showed greater disruptions in calcium regulation (as assessed via fluorescent imaging analysis prior to and following 750 microm oxotremorine) than those transfected with M3 or M5 AChR. We also examined the effects of calcium channel antagonists (e.g., Nifedipine) or antioxidants (vitamin E) in protecting against the deleterious effects of Abeta. Results are discussed in terms of differences in MAChR structure that could lead to selective Abeta effects and the possible implications on memory and AbetaPP processing.