Project

Discipline

kainic acid; epilepsy; age-related dementia; neuro-immune interactions; amyloid precursor protein; neurodegeneration; microglia; Alzheimer's disease; temporal lobe epilepsy; anti-inflammatory drug

Lead
Dieses Projet fokussiert auf die Interaktionen zwischen epileptischen Anfällen und die Pathophysiologie der sporadischen, altersbedingten Alzheimersche-Krankheit
Lay summary
Die Alzheimersche-Krankheit (AD) ist die häufigste, altersabhängige Demenzerkrankung, gekennzeichnet von schweren Gedächtnisstörungen und kognitive Beeinträchtigung. AD und Epilepsien werden meistens als getrennte klinische Entitäten betrachtet, mit eigenartiger Ätiologie, Pathophysiologie, und Behandlung. Es gibt aber klinische Berichte, dass AD und andere altersabhängige Demenzen mit einem hohen Risiko von spontanen epileptischen Anfällen verbunden sind, insbesondere in den frühen Krankheitsstadien. Nicht-detektiere Anfälle könnten also bei AD-Patienten häufiger vorkommen als bis anhin angenommen, und sie könnten kognitive Fähigkeiten beeinflussen. Insbesondere könnten die oft-beobachteten Fluktuationen der kognitiven Leistungen bei Krankheitsbeginn durch epileptische Anfälle verursacht sein. Experimentelle und klinische Forschung in den letzten Jahren haben gezeigt, dass Entzündungen und immunabhängige Vorgänge eine wichtige Rolle bei der Entwicklung von sporadischer, nicht-familiärer Form der AD spielen. Insbesondere wurde gezeigt, dass wiederholte systemische Entzündungen, provoziert durch Virus-ähnliche Infektionen, die Erscheinung von AD-like Pathologie (Entstehung von Ab Plaques und Tau Hyperphosphorylierung) im Gehirn von adulten Mäusen stark begünstigen. Gleicherweise wurde gezeigt, dass die Pathophysiologie von verschiedenen Epilepsien,  wie zum Beispiel, der Schlafenlappenepilepsie (TLE), stark von Immunreaktionen beeinflusst wird. Diese Mechanismen beinhalten direkte Interaktionen zwischen Zellen des Immun- und des Nervensystems, sowie die Aktion von pro- und anti-inflammatorischen Zytokinen und Chemokinen, welche die Erregbarkeit von Neuronen stark beeinflussen. In unseren Labor, haben wir zu diesen Resultaten beigetragen (Kristic et al., 2012, J Neuroinflammation 9:151; Zattoni et al., 2011, J Neurosci 31, 4037) und wir haben Maus-Modellen der Schlafenlappenepilepsie und der sporadischen AD entwickelt. Wir schlagen hier vor, diese Modelle zu kombinieren, um die Interaktionen zwischen AD und Epilepsie zu untersuchen. Spezifisch werden wir folgenden Fragen nachgehen: • Erstens werden wir bestimmen, ob Immunstimulationen durch Virus-ähnliche Substanzen, welche Symptome der AD auslösen, ebenfalls epileptische Anfälle provozieren. Diese Untersuchungen werden wir in Modellen von sporadischer und familiärer AD durchführen.  • Zweitens werden wir untersuchen, ob Anfälle die AD-like Pathologie verschlimmern, und ob die AD die Prädisposition für epileptische Anfälle erhöht. • Drittens werden wir untersuchen, welche Komponente des Immunsystems zur Pathologie von beiden Krankheiten beitragen. Dafür werden wir den Einfluss von Immundefiziens in Mäusen, und nach pharmakologischer Behandlung testen. Bedeutung: Dieses Projekt wird eine Problematik erforschen, die bisher nur wenig Aufmerksamkeit bekommen hat, aber die für die Pathophysiologie der AD hochrelevant sein könnte. Spezifisch erwarten wir, Mechanismen zu identifizieren, welche die Anfälligkeit von Anfällen erhöhen, und, umgekehrt zu erläutern, wie lokale Entzündungen und wiederholte epileptische Aktivität die Evolution der AD-Pathologie begünstigen könnten. Die erfolgreiche Vollendung dieses Projekt soll neue Kenntnisse liefern zu Gunsten der klinischen Behandlung von AD-Patienten, insbesondere ob anti-inflammatorische und anti-epileptische Medikamente beitragen können, ihre kognitive Beeinträchtigungen zu mindern.

Direct link to Lay Summary

Last update: 25.03.2013

Lead
This project aims to investigate the interactions between epileptic seizures and the pathophysiology of Alzheimer's disease.
Lay summary
Alzheimer’s disease (AD) is the most prevalent age-related dementia, causing strongly disabling loss of memory and impairment of cognitive abilities. AD and epilepsies are often viewed as separate clinical entities, with distinct etiology, pathophysiology, and treatment. However, clinical reports show that AD and other aging-related forms of dementia are associated with a high risk of unprovoked epileptic seizures, particularly prominently during early stages of the disease. Undetected epileptic seizures in AD patients might be more frequent than generally assumed and contribute to affect cognition. In particular, fluctuations in cognitive performance at early disease stages might be due to non-convulsive seizures. Conversely, unrecognized epilepsy patients frequently present recurrent memory disturbances, closely resembling clinical features of early stages of AD. Experimental and clinical research in recent years has demonstrated that inflammation and immune-related processes play a key role in the development of late-onset, non-familial AD, which affects the vast majority of AD patients. In particular, repeated systemic inflammation induced by viral-like infections can precipitate AD-like neuropathology (formation of Ab plaques and Tau hyperphosphorylation) in the brain of aging mice. Likewise, the pathophysiology of several forms of acquired epilepsies (occurring, for example, after a brain lesion), as well as temporal lobe epilepsy (TLE), has been shown to involve a major contribution of both innate and acquired immunity. These mechanisms involve direct interactions between immune cells and brain cells, as well as the action of pro- and anti-inflammatory cytokines and chemokines, with strong effects on neuronal excitability. In our laboratory, we have contributed to these findings (Kristic et al., 2012, J Neuroinflammation 9:151; Zattoni et al., 2011, J Neurosci 31, 4037) and have experimental mouse models of familial and late-onset AD, as well as a model of TLE induced by injection of a neurotoxin, kainic acid, into the brain of adult mice. Here, we propose to combine these two approaches for testing the interactions between AD and epilepsy. Specifically, we will address the following issues: • First, we will determine whether immune challenges that precipitate AD-like pathology in both transgenic and immune-sensitized wild type mice enhance their seizure susceptibility.  • Second, we will investigate whether seizures worsen AD-like pathology and whether AD predisposition enhances the effects of seizures.  • Third, we will test whether innate and adaptive immunity contribute to these effects in both pathologies, using a combination of immunodeficient mice and immunosuppressant pharmacological treatments. Significance: This project will explore in detail an area that has received relatively little attention so far, but which could be highly relevant for the pathophysiology of both sporadic and familial forms of AD. Specifically, we expect to identify mechanisms contributing to enhanced seizure susceptibility in AD and, conversely, highlight the pathways through which local inflammation and recurrent seizure activity might impact on the evolution of AD-like pathology.  Successful completion of this work will result in a significant new knowledge of relevance for therapy and management of AD patients, by showing whether anti-inflammatory and/or anti-epileptic drug treatment can prevent seizures and ensuing cognitive deterioration.

Direct link to Lay Summary

Last update: 25.03.2013

Active participation

Number	Title	Start	Funding scheme

Background: Alzheimer's disease (AD) is the most prevalent age-related dementia and represents a major health burden in Western societies. Several lines of evidence indicate that AD is frequently associated with epilepsy. Clinically, a large fraction of AD patients have (undetected) limbic seizures that markedly affect their cognitive performances. Experimental studies indicate that seizures occur in several lines of transgenic AD mice and result from abnormal amyloid precursor protein (APP) function/processing. Furthermore, seizures contribute to accelerated cognitive decline and neurodegeneration by favoring A? aggregation and Tau hyper-phosphorylation. Accordingly, AD and epilepsy might be intimately linked by a vicious circle, whereby seizures worsen AD pathology, which in turn promotes seizure activity. Our recent work in murine AD models revealed that exposure of pregnant wild type mice to the cytokine releaser polyriboinosinic-polyribocytidilic acid (PolyI:C), mimicking a severe viral infection, accelerates aging in their offspring and has major consequences for the development of AD-like neuropathology. Most strikingly, exposing adult transgenic AD mice to PolyI:C likewise precipitates APP aggregation and Tau hyper-phosphorylation. We also have developed a mouse model of temporal lobe epilepsy based on intra-hippocampal injection of kainic acid. This model is characterized by severe neurodegeneration and life-long occurrence of spontaneous non-convulsive recurrent seizures. Further, we have shown that this epileptic focus causes enduring local inflammation as well as activation of both innate and adaptive immunity, which contribute to epileptogenesis and seizure onset. Therefore, combining these experimental approaches should provide a unique opportunity to investigate the role of epileptic seizures and their associated immune responses for AD onset and progression. Moreover, subjecting familial and sporadic AD mouse models to the same seizure-provoking paradigms will allow testing the hypothesis that seizures drive AD-like pathology and exploring the role of immune mediators in this chain of pathophysiological events.Aims: This grant proposal aims at exploring the links between AD and epilepsy from three different perspectives. First, we will determine whether immune challenges that precipitate AD-like pathology in both transgenic and sensitized wild type mice enhance their seizure susceptibility. Second, we will investigate whether seizures worsen AD-like pathology and whether AD predisposition enhances the effects of seizures. Third, we will test whether innate and adaptive immunity contribute to these effects in both pathologies, using a combination of immunodeficient mice and immunosuppressant pharmacological treatments.Research plan: The project is subdivided into five experiments combining PolyI:C-mediated immune challenges with kainic acid injection in wild type and transgenic AD mice. Functionally, seizures will be characterized by intrahippocampal EEG recordings. Progression of AD-like symptoms will be monitored histologically and biochemically focusing on APP processing, formation of amyloid plaques, and Tau hyper-phosphorylation. Innate and adaptive immune responses will be assessed immunohistochemically with appropriate markers, as well as by monitoring leukocytes by FACS and blood and tissue cytokines/chemokines by multiplex ELISA. Immunodeficient mice lacking either T and B lymphocytes or the MHCII complex will be used to provide possible causal relationships between immune responses and seizure/AD phenotypes. Finally, chronic treatments with anti-inflammatory or immunosupressant drugs will be carried out to provide proof-of-principle evidence for therapeutic strategies targeting the immune system to prevent AD-like progression in these mouse models.Significance: This project will explore in detail an area that has received relatively little attention so far, but which could be highly relevant for the pathophysiology of both sporadic and familial forms of AD. Specifically, we expect to identify mechanisms contributing to enhanced seizure susceptibility in AD and, conversely, highlight the pathways through which local inflammation and recurrent seizure activity might impact on the evolution of AD-like pathology.