Background: Alzheimer’s disease (AD) amyloid plaques consist of ag- gregated polypeptide of 39-42 amino acids, known as amyloid-beta (Abeta) peptides, that have been shown to cause synaptic dysfunction (Selkoe, 2002) and memory loss (Cleary et al, 2005). However, Abeta is normally produced in the brain where its levels are likely to be regulated by synaptic activity (Cirrito et al, 2003; Kamenetz et al, 2003) and are estimated to be in the picomolar range. Methods: We investigated the possible role for picomolar levels of Abeta in the regulation of CA1-hippocampal long-term potentiation (LTP), a widely studied cellular model of learning and mem- ory, and contextual fear learning (FC), an associative type of memory. Results: We found that Abeta42 in the picomolar range (200pM) enhances both LTP and FC. The study of post-tetanic potentiation (PTP), a type of short-term synaptic plasticity that reflects the transient increase of gluta- mate release during brief periods of high-frequency stimulation (Zucker et al, 2002), revealed that 200pM Abeta42 enhances transmitter release during the tetanus. Given that Abeta regulates alpha7-nicotinic acetylcholine receptors (nAchRs) activating them when administered in the low picomolar range (Dougherty et al, 2003), and that these receptors, in turn, promote trans- mitter release (Wonnacott, 1997), we tested if the A-induced increase in PTP was blocked by perfusion of the slices with the non-selective nAchR antagonist mecamylamine and the highly specific alpha7-nAchR antagonist alpha-bungarotoxin. We found that Abeta42 no longer increased PTP during the tetanus. Moreover, perfusion with 200pM Abeta42 failed to enhance LTP and FC in mice lacking alpha7-nAchRs suggesting that the mechanism of action of Abeta42 on synaptic plasticity and memory involves alpha7-nAChRs. Consistent with these findings, administration of 200pM Abeta42 in APP knock-out mice was still capable of enhancing LTP. Conclusions: We propose that positive and negative effects of Abeta on synaptic function and memory represent a continuum, in which low concentrations of Abeta play a positive modulatory role upon synaptic transmission and memory, and that high concentrations of Abeta may produce detrimental effects that can culminate in dementia.

Amyloid-beta peptide as a positive modulator of synaptic plasticity and memory

PUZZO, DANIELA;PALMERI, Agostino;
2008

Abstract

Background: Alzheimer’s disease (AD) amyloid plaques consist of ag- gregated polypeptide of 39-42 amino acids, known as amyloid-beta (Abeta) peptides, that have been shown to cause synaptic dysfunction (Selkoe, 2002) and memory loss (Cleary et al, 2005). However, Abeta is normally produced in the brain where its levels are likely to be regulated by synaptic activity (Cirrito et al, 2003; Kamenetz et al, 2003) and are estimated to be in the picomolar range. Methods: We investigated the possible role for picomolar levels of Abeta in the regulation of CA1-hippocampal long-term potentiation (LTP), a widely studied cellular model of learning and mem- ory, and contextual fear learning (FC), an associative type of memory. Results: We found that Abeta42 in the picomolar range (200pM) enhances both LTP and FC. The study of post-tetanic potentiation (PTP), a type of short-term synaptic plasticity that reflects the transient increase of gluta- mate release during brief periods of high-frequency stimulation (Zucker et al, 2002), revealed that 200pM Abeta42 enhances transmitter release during the tetanus. Given that Abeta regulates alpha7-nicotinic acetylcholine receptors (nAchRs) activating them when administered in the low picomolar range (Dougherty et al, 2003), and that these receptors, in turn, promote trans- mitter release (Wonnacott, 1997), we tested if the A-induced increase in PTP was blocked by perfusion of the slices with the non-selective nAchR antagonist mecamylamine and the highly specific alpha7-nAchR antagonist alpha-bungarotoxin. We found that Abeta42 no longer increased PTP during the tetanus. Moreover, perfusion with 200pM Abeta42 failed to enhance LTP and FC in mice lacking alpha7-nAchRs suggesting that the mechanism of action of Abeta42 on synaptic plasticity and memory involves alpha7-nAChRs. Consistent with these findings, administration of 200pM Abeta42 in APP knock-out mice was still capable of enhancing LTP. Conclusions: We propose that positive and negative effects of Abeta on synaptic function and memory represent a continuum, in which low concentrations of Abeta play a positive modulatory role upon synaptic transmission and memory, and that high concentrations of Abeta may produce detrimental effects that can culminate in dementia.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/56648
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