Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Institut für Neurowissenschaften, Technische Universität München (TUM), 80802 München, Germany.
Science (Impact Factor: 33.61). 10/2008; 321(5896):1686-9. DOI: 10.1126/science.1162844
Source: PubMed


The neurodegeneration observed in Alzheimer's disease has been associated with synaptic dismantling and progressive decrease in neuronal activity. We tested this hypothesis in vivo by using two-photon Ca2+ imaging in a mouse model of Alzheimer's disease. Although a decrease in neuronal activity was seen in 29% of layer 2/3 cortical neurons, 21% of neurons displayed an unexpected increase in the frequency of spontaneous Ca2+ transients. These "hyperactive" neurons were found exclusively near the plaques of amyloid beta-depositing mice. The hyperactivity appeared to be due to a relative decrease in synaptic inhibition. Thus, we suggest that a redistribution of synaptic drive between silent and hyperactive neurons, rather than an overall decrease in synaptic activity, provides a mechanism for the disturbed cortical function in Alzheimer's disease.

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    • "Several studies have also shown increased neuronal hyperactivity and excitability in the cortex of young APP transgenic mice before or when the first amyloid plaques appear ( Palop et al . , 2007 ; Busche et al . , 2008 ; Minkeviciene et al . , 2009 ; Gurevicius et al . , 2013 ) . This increased excitability is likely responsible for spontaneous epileptic seizures and premature death of APP mice ( Palop et al . , 2007 ; Minkeviciene et al . , 2009 ) . Enhancement of neuronal activity associated with early pathological and memory changes in AD mouse FIG"
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    ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.
    Frontiers in Cellular Neuroscience 08/2015; 9. DOI:10.3389/fncel.2015.00318 · 4.29 Impact Factor
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    • "In the years preceding AD diagnosis, a hyperactivity of the distributed memory network is often observed in those at risk for AD (Bookheimer et al. 2000; Bondi et al. 2005; Bassett et al. 2006; Filippini et al. 2009; Quiroz et al. 2010; Sperling et al. 2010). Although originally this hyperactivity was believed to serve a compensatory function for deteriorating circuitry (Bondi et al. 2005), more recent evidence suggests this hyperactivity may be indicative of excitotoxicity, could directly contribute to cognitive impairment, and may even be permissive for the development of AD (Mackenzie and Miller 1994; Kamenetz et al. 2003; Busche et al. 2008, Koh et al. 2010; Bakker et al. 2012; Vossel et al. 2013; Yamada et al. 2014). "
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    ABSTRACT: Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis (ALS) that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1), the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2015; 135(2). DOI:10.1111/jnc.13230 · 4.28 Impact Factor
    • "airment in both aMCI and AD mouse models . This view is further supported by data from the double - transgenic APP23 Â PS45 mice , overexpressing the APPswe and PS1G384A mutations ( Sturchler - Pierrat et al . , 1997 ) . These mice show neuronal hyperactivity exclusively near Ab plaques , as was demonstrated by in vivo 2 - photon calcium imaging ( Busche et al . , 2008 ) . Hyperactivity of neurons in the visual cortex of these mice was coupled to defects in neuronal tuning for the orientation of visual stimuli ( Grienberger et al . , 2012 ) . Interestingly , the fraction of hyperactive neurons was already dramatically increased in the CA1 area before the onset of plaque pathology , compared with contr"
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    ABSTRACT: Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 09/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.014 · 5.01 Impact Factor
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