Amyloid ß-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons.

Amyloid ß protein (Aß) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aß and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aß-induced damage of nAChRs. This study investigated the effects of Aß fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4ß2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-µM) of Aß25-35, Aß31-35, or Aß35-31 alone did not trigger any membrane current, but pretreatment with 1 µM Aß25-35 and Aß31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine-induced currents were also reversibly suppressed by the Aß pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both α7 and α4ß2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aß treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aß in AD. In addition, the similar suppression of nAChR currents by Aß25-35 and Aß31-35 suggests that the sequence 31-35 in Aß molecule may be a shorter active center responsible for the neurotoxicity of Aß in AD.