Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides.
Although it is generally believed that amyloid beta (Abeta) peptides contribute to the pathogenesis of Alzheimer's disease, the precise role of these peptides in the development of memory loss of Alzheimer's disease, has not been fully understood. The present study examined the effect of several synthetic Abeta peptides on long-term potentiation (LTP), a cellular model of learning and memory, in rat hippocampal slices. Brief perfusion of slices with low concentrations (200 nM or 1 microM) of Abeta(1-42), Abeta(1-40) or their active fragment Abeta(25--35) significantly inhibited LTP induction without affecting the basal synaptic transmission and posttetanic potentiation in the dentate medial perforant path. A similar effect of Abeta(25-35) was also observed in the Schaffer collateral-CA1 pathway. When comparing actions of several Abeta variants derived from Abeta(25-35), the N-terminal sequence of Abeta(25-35) was found necessary for inhibiting LTP. In addition, Abeta variants lacking neurotoxic action and aggregating property were also able to block LTP, suggesting that this effect was neurotoxicity independent. Our findings demonstrated that subneurotoxic concentrations of Abeta peptides could strongly suppress long-term synaptic plasticity in the hippocampus. Such an effect might underlie the memory deficits seen in Alzheimer's disease before neuronal cell loss.
Chen
Q S
QS
Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California-Los Angeles, Los Angeles 90024-1759, USA.
Kagan
B L
BL
Hirakura
Y
Y
Xie
C W
CW
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35)