Amyloid β‐peptide Aβ_1–42 but not Aβ_1–40 attenuates synaptic AMPA receptor function

Abstract

Abstract The brains of Alzheimer's disease (AD) patients have large numbers of plaques that contain amyloid beta (Aβ) peptides which are believed to play a pivotal role in AD pathology. Several lines of evidence have established the inhibitory role of Aβ peptides on hippocampal memory encoding, a process that relies heavily on α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor function. In this study the modulatory effects of the two major Aβ peptides, Aβ 1–40 and Aβ 1–42 , on synaptic AMPA receptor function was investigated utilizing the whole cell patch clamp technique and analyses of single channel properties of synaptic AMPA receptors. Bath application of Aβ 1–42 but not Aβ 1–40 reduced both the amplitude and frequency of AMPA receptor mediated excitatory postsynaptic currents in hippocampal CA1 pyramidal neurons by ∼60% and ∼45%, respectively, in hippocampal CA1 pyramidal neurons. Furthermore, experiments with single synaptic AMPA receptors reconstituted in artificial lipid bilayers showed that Aβ 1–42 reduced the channel open probability by ∼42% and channel open time by ∼65% and increased the close times by several fold. Aβ 1–40 , however, did not show such inhibitory effects on single channel properties. Application of the reverse sequence peptide Aβ 42–1 also did not alter the mEPSC or single channel properties. These results suggest that Aβ 1–42 but not Aβ 1–40 closely interacts with and exhibits inhibitory effects on synaptic AMPA receptors and may contribute to the memory impairment observed in AD. Synapse 61:367‐374, 2007. © 2007 Wiley‐Liss, Inc.