Amyloid beta-peptide Abeta(1-42) but not Abeta(1-40) attenuates synaptic AMPA receptor function.
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.
Parameshwaran
Kodeeswaran
K
Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Sims
Catrina
C
Kanju
Patrick
P
Vaithianathan
Thirumalini
T
Shonesy
Brian C
BC
Dhanasekaran
Muralikrishnan
M
Bahr
Ben A
BA
Suppiramaniam
Vishnu
V
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018091:Receptors, AMPA; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid