Continuous intracerebroventricular infusion of β-amyloid peptide 1-40 (Aβ(1-40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. β-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from Aβ-infused brain. Throughout this study, an effort was made to address whether the α7 nicotinic acetylcholine receptor (α7nAChR), which is believed to be a primary target of Aβ [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Aβ (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155-1161.], is responsible for the deficits in synaptic plasticity observed in the Aβ-infused rats. First, we found that Aβ-infusion markedly depressed the response of α7nAChR to a selective α7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of α7nAChR with either methyllycaconitine (MLA) or α-bungarotoxin (α-BTX) in control rats inhibited LTP induction, suggesting that the activation of α7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Aβ-infused rats with 10 μM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Aβ-impaired LTP and PPF arise as a consequence of dysfunctional α7nAChR, and that α7nAChR may be an important target to help ameliorate AD patient cognitive deficits.
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