Amyloid beta-peptide Abeta(1-42) but not Abeta(1-40) attenuates synaptic AMPA receptor function.

Parameshwaran K, Sims C, Kanju P, Vaithianathan T, Shonesy BC, Dhanasekaran M, Bahr BA, Suppiramaniam V
Synapse. 2007 61 (6): 367-74

PMID: 17372971 · DOI:10.1002/syn.20386

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

MeSH Terms (17)

Alzheimer Disease Amyloid beta-Peptides Animals Excitatory Postsynaptic Potentials Glutamic Acid Hippocampus Ion Channel Gating Organ Culture Techniques Patch-Clamp Techniques Peptide Fragments Pyramidal Cells Rats Rats, Sprague-Dawley Receptors, AMPA Synapses Synaptic Transmission Synaptosomes

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