Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Neurobiology of aging (Impact Factor: 5.01). 10/2009; 32(9):1725-9. DOI: 10.1016/j.neurobiolaging.2009.09.002
Source: PubMed


Alterations in the processing of the amyloid precursor protein (APP) lead to familial Alzheimer's disease (AD). AD patients exhibit increased seizure susceptibility and alterations in their EEGs, which suggests that APP and its metabolites may modulate neuronal networks. Here we demonstrate that transgenic mice overexpressing APP intracellular domain (AICD) and its binding partner Fe65 exhibit abnormal spiking events and a susceptibility to induced seizures. These abnormalities are not observed in PDAPP(D664A) mice, which express high Aβ levels but harbor a mutation in the APP intracellular domain. These data suggest that alterations in the levels of AICD contribute to network dysfunction in AD.

Download full-text


Available from: Daniel L Vogt, May 07, 2014
  • Source
    • "Importantly, epileptic activity may also be more prevalent in the early stages of 'sporadic' late-onset AD than was previously thought (Vossel et al., 2013), but the underlying mechanisms are poorly understood. In line with the increasing awareness of the occurrence of subclinical and clinical seizures in AD patients, several laboratories have reported spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation (Palop et al., 2007; Westmark et al., 2008; Minkeviciene et al., 2009; Vogt et al., 2011; Bezzina et al., 2015). Such studies suggest that the hyperexcitability induced by oligomeric Aβ assemblies (oAβ) may involve depolarization of the resting membrane potential (Minkeviciene et al., 2009), depression of the slow after-hyperpolarization (Driver et al., 2007), depletion of calbindin and ectopic expression of neuropeptide Y (Palop et al., 2007) and upregulation of α7-nAChR function (Liu et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAβ increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.
    Full-text · Article · Nov 2015 · Neurobiology of Disease
    • "own to affect development , synaptic plasticity and cytoskeletal dynamics . AICD / AID has also been demonstrated to modulate intracellular homeostasis of cal cium and ATP ( Hamid et al . , 2007 ) , to control neuronal net works , microtubule stabilization and cell death ( Kinoshita et al . , 2003 ; Nakaya and Suzuki , 2006 ; Ghosal et al . 2009 ; Vogt et al . , 2011 ; Ohkawara et al . , 2011 ) , to regulate transcriptional activation of Ab - degrading enzyme neprily sin ( Pardossi - Piquard et al . , 2005 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: For several years Amyloid-beta peptide (Aβ) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aβ levels have been unsuccessful. Moreover, Aβ is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aβ and its physiological receptors, focusing on α7-nAchRs. According to this vision, when Aβ cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aβ removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aβ in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Aug 2015 · Neuroscience
  • Source
    • "In a recent study, it has been shown that overexpression of the APP intracellular domain (AICD) increases the susceptibility to spontaneous seizures, deficits in LTP and seizure-induced drug generation (Vogt et al., 2011). Moreover, in these models the seizure susceptibility and severity does not depend on the presence of A␤, but on the levels of AICD; higher AICD levels result in the most severe seizures (Vogt et al., 2011). This effect is independent of high levels of A␤, because mice overexpressing hAPP but with a mutation in AICD do not generate deficits in LTP or memory, despite the high level of A␤ (Galvan et al., 2006; Saganich et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.
    Full-text · Article · May 2013 · Ageing research reviews
Show more