Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms
Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: .Epilepsy & Behavior (Impact Factor: 2.26). 01/2013; 26(3). DOI: 10.1016/j.yebeh.2012.11.040
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".
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ABSTRACT: Purpose Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of epilepsies in adults. The calcium homeostasis modulator 1gene (CALHM1) has been considered one of the candidate genes that play a role in epileptogenesis due to its function in calcium homeostasis and amyloid β (Aβ) regulation. Recently, the association of a single nucleotide polymorphism (rs11191692) of CALHM1 has been reported to be associated with MTLE in Han Chinese, but independent replication is needed. In the present study, rs11191692 and rs2986017 of CALHM1 were determined in 512 MTLE patients and 412 control subjects to investigate the possible involvement of CALHM1 in the etiology of MTLE. Methods Genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism method. Major statistical analyses were performed by SAS. Results No significant differences in the genotypic or allelic frequencies of both single-nucleotide polymorphisms were revealed between subjects with and without MTLE (rs11191692: P = 0.890 and 0.230; rs2986017: P = 0.581 and 0.072). Further stratification analysis by gender and age, and analysis of clinical features in relation to MTLE also yielded negative results. Conclusion rs11191692 and rs2986017 of CALHM1 does not contribute substantially to MTLE in Han Chinese.Seizure 01/2013; 23(3). DOI:10.1016/j.seizure.2013.11.010 · 1.82 Impact Factor
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ABSTRACT: Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta-burst stimulation; TBS). However, a different LTP induction protocol was unaffected by AQP4 deletion. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and selective role of AQP4 in synaptic plasticity and spatial memory, and underscore the growing appreciation of the role of glial cells in functions typically attributed to neurons. Implications for epilepsy are discussed because of the previous evidence that AQP4 influences seizures, and the role of synaptic plasticity in epileptogenesis.Neurochemistry International 05/2013; 63(7). DOI:10.1016/j.neuint.2013.05.003 · 3.09 Impact Factor
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ABSTRACT: Neurons have been the natural focus of discussion for most of the history of research on seizures and epilepsy. Simply stated, epilepsy is a disease of sporadic, progressive disruption of neuronal activity. Thus causes and therapies for epilepsy have been naturally aimed at the obvious manifestation of disease: neuronal dysfunction. However, over the last two decades a new view is beginning to emerge that is defining the dependence of neuronal function and seizure susceptibility on glia. This view changes the definition of epilepsy as a disease of neurons to a disease of a heterogeneous neuronal-glial network. This new glial focus is suggesting new opportunities to treat the nearly 1/3 of individuals who do not respond to traditional antiepileptic drug (AEDs) therapies as well as suggesting ways to reduce the many unwanted side effects of AEDs.Neurochemistry International 09/2013; 63(7). DOI:10.1016/j.neuint.2013.09.004 · 3.09 Impact Factor
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