Abstract
The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer’s disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.
Highlights
Group while potentiation was significantly reduced in the 3 hour and 12–24 hour groups (C)
When we investigated the effects of 200 pM Aβon synaptic plasticity for a variable time in 10–13 days in vitro (DIV) cultures, we found a significant effect of Aβtreatment following exposure to 200 μM glutamate in Mg2+-free solution for 30 sec, with 1 hour exposure increasing plasticity, reaching significance in the first 8 min after glutamate exposure compared to vehicle (Fig. 1B)
The facilitation of synaptic plasticity by 200 pM Aβis reverted into a block of long lasting synaptic potentiation when the peptide is present for extended periods of time
Summary
Group while potentiation was significantly reduced in the 3 hour and 12–24 hour groups (C). The peptide has been found to be released endogenously during neuronal activity[22,23] and to enhance synaptic plasticity and memory formation when administered at picomolar doses[24,25,26] which presumably mimic the physiological concentration of the peptide in the brain[24,27,28]. Aβturned out to be required for normal synaptic plasticity and memory[25,29,30]. These findings lead to the question as to how the function of Aβmight switch from beneficial to harmful. We investigated whether the well-known facilitatory effects of picomolar Aβon synaptic plasticity and memory[24] might change over time.
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