Abstract
IntroductionRecent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.MethodsTransgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.ResultsWe report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.ConclusionsOur data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-015-0110-9) contains supplementary material, which is available to authorized users.
Highlights
Recent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction
Our data indicate that Spike-wave discharge (SWD) are associated with poor cognitive performance in APP/PS1 mice, but that the reduction of this abnormal network activity does not reliably predict therapeutic reversal of age-associated impairments in spatial memory in this mouse model
On the basis of EEG morphology, no differences in SWDs were observed between mouse strains, and the frequency of SWDs was not found to be significantly different between the two mouse models (APP/PS1 mean: 5 ± 1 SWDs/hr versus 3xTg-AD mean: 11 ± 6 SWDs/hr; P = 0.2 by Student’s t-test)
Summary
Recent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Several groups, including ours, have shown that mice overexpressing the amyloid precursor protein (APP) have seizures [4,5,6] These findings have led to the hypothesis that amyloid-β (Aβ), the peptide derived from APP and widely believed to play a critical role in AD pathogenesis, may trigger neuronal hyperexcitability, seizures, and worsen neuronal dysfunction in AD. This hypothesis was partly tested in two recent studies where transgenic AD mice underwent chronic treatment with the antiepileptic drug (AED) levetiracetam [7,8]. The same drug was recently shown to improve select hippocampal function in human subjects diagnosed
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