Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms
ABSTRACT Seizures in patients with Alzheimer's disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid β (Aβ) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neurobiological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying mechanisms may exist for at least some of the aspects of AD that are also found in TLE. This article is part of a Special Issue entitled "Translational Epilepsy Research".
- SourceAvailable from: Marco Weiergräber[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.Neural Plasticity 03/2015; 2015. DOI:10.1155/2015/781731 · 3.60 Impact Factor
Article: Seizures in Alzheimer’s disease[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease increases the risk for late-onset seizures and neuronal network abnormalities. An elevated co-occurrence of Alzheimer's disease and seizures has been established in the more prevalent sporadic form of Alzheimer's disease. Recent evidence suggests that nonconvulsive network abnormalities, including seizures and other electroencephalographic abnormalities, may be more commonly found in patients than previously thought. Patients with familial Alzheimer's disease are at an even greater risk for seizures, which have been found in patients with mutations in PSEN1, PSEN2, or APP, as well as with APP duplication. This review also provides an overview of seizure and electroencephalography studies in Alzheimer's disease mouse models. The amyloid-β peptide has been identified as a possible link between Alzheimer's disease and seizures, and while amyloid-β is known to affect neuronal activity, the full-length amyloid precursor protein (APP) and other APP cleavage products may be important for the development and maintenance of cortical network hyperexcitability. Nonconvulsive epileptiform activity, such as seizures or network abnormalities that are shorter in duration but may occur with higher frequency, may contribute to cognitive impairments characteristic of Alzheimer's disease, such as amnestic wandering. Finally, the review discusses recent studies using antiepileptic drugs to rescue cognitive deficits in Alzheimer's disease mouse models and human patients. Understanding the mechanistic link between epileptiform activity and Alzheimer's disease is a research area of growing interest. Further understanding of the connection between neuronal hyperexcitability and Alzheimer's as well as the potential role of epileptiform activity in the progression of Alzheimer's disease will be beneficial for improving treatment strategies. Copyright © 2014. Published by Elsevier Ltd.Neuroscience 12/2014; 286. DOI:10.1016/j.neuroscience.2014.11.051 · 3.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Objective: Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer’s disease. We wanted to determine if tau reduction may also be of benefit in intractable genetic epilepsies. Methods: We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav1.1. We genetically deleted one or two Tau alleles in mice carrying an Nav1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, EEG recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays. Results: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only one Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. Interpretation: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies.Annals of Neurology 09/2014; 76(3). DOI:10.1002/ana.24230 · 11.91 Impact Factor