Amyloid β-Peptide Aβ1−42 But Not Aβ1−40 Attenuates Synaptic AMPA Receptor Function

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ABSTRACTThe 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 αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function. In this study the modulatory effects of the two major Aβ peptides, Aβ1−40 and Aβ1−42, 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 Aβ1−42 but not Aβ1−40 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 Aβ1−42 reduced the channel open probability by ∽42% and channel open time by ∽65% and increased the close times by several fold. Aβ1−40, however, did not show such inhibitory effects on single channel properties. Application of the reverse sequence peptide Aβ42−1 also did not alter the mEPSC or single channel properties. These results suggest that Aβ1−42 but not Aβ1−40 closely interacts with and exhibits inhibitory effects on synaptic AMPA receptors and may contribute to the memory impairment observed in AD.

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