Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice

Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, Charlestown, MA 02129, USA.
Science (Impact Factor: 33.61). 03/2009; 323(5918):1211-5. DOI: 10.1126/science.1169096
Source: PubMed


Although senile plaques focally disrupt neuronal health, the functional response of astrocytes to Alzheimer's disease pathology is unknown. Using multiphoton fluorescence lifetime imaging microscopy in vivo, we quantitatively imaged astrocytic calcium homeostasis in a mouse model of Alzheimer's disease. Resting calcium was globally elevated in the astrocytic network, but was independent of proximity to individual plaques. Time-lapse imaging revealed that calcium transients in astrocytes were more frequent, synchronously coordinated across long distances, and uncoupled from neuronal activity. Furthermore, rare intercellular calcium waves were observed, but only in mice with amyloid-beta plaques, originating near plaques and spreading radially at least 200 micrometers. Thus, although neurotoxicity is observed near amyloid-beta deposits, there exists a more general astrocyte-based network response to focal pathology.

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Available from: Kishore V. Kuchibhotla, Jun 20, 2014
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    • "lammation may disturb normal neuronal functions and impede regeneration ( Kinouchi et al . , 2003 ; Menet et al . , 2003 ; Pekny et al . , 2014 ; Widestrand et al . , 2007 ; Wilhelmsson et al . , 2004 ) . It may therefore be necessary to study reactive astrocytes with and without IF at the functional level of intracellular cal - cium homeostasis ( Kuchibhotla et al . , 2009 ) , and their GABA - and glutamate - sensitivity or intracellular coupling ( Peters et al . , 2009 ) to disclose functions attributable to IFs ."
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    ABSTRACT: Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Glia 03/2015; 63(6). DOI:10.1002/glia.22800 · 6.03 Impact Factor
    • "Reproduced with permission from (Verkhratsky et al., in press). AD animals (APP/PS1 mice carrying mutated genes for APP and PS1) revealed abnormally frequent [Ca 2+ ] i oscillations in reactive astrocytes associated with senile plaques: these abnormal Ca 2+ transients gave rise to aberrant Ca 2+ waves spreading through coupled astrocytes (Kuchibhotla et al., 2009). In another AD model, in mice expressing Swedish mutation of the APP gene, astrocytes showed higher frequency of spontaneous oscillations even before the appearance of amyloid plaques (Takano et al., 2007). "
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    ABSTRACT: Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contribute to the ageing of the brain and to neurodegenerative diseases. Changes in astroglia in ageing and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter homeostatic reserve of the brain and contribute to early cognitive deficits. At the later stages of AD reactive astrocytes are associated with neurite plaques, the future commonly found in animal models and in human diseased tissue. In animal models of the AD reactive astrogliosis develops in some (e.g. in the hippocampus) but not in all regions of the brain. For instance, in entorhinal and prefrontal cortex astrocytes to not mount gliotic response to emerging β-amyloid deposits. This deficits in reactivity coincides with higher vulnerability of these regions to AD-type pathology. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at prevention and cure of neurodegenerative disorders. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; DOI:10.1016/j.neuroscience.2015.01.007 · 3.36 Impact Factor
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    • "Reactive astrocytes in AD animal models show aberrant physiology. These astrocytes, associated with senile plaques, were reported to generate spontaneous Ca 2+ oscillations and abnormal Ca 2+ waves (Kuchibhotla et al. 2009). Molecular cues initiating astroglial reactivity in AD are multiple and may include extracellular β-amyloid as well as factors released by damaged cells. "
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    ABSTRACT: Abstract Neurodegenerative diseases, which affect almost exclusively humans, are chronic disorders that ultimately result in atrophy of the brain and profound cognitive deficit. Neurodegenerative process reflects a profound failure of brain homeostasis. Neuroglial cells, being primarily the cells responsible for brain homeostasis and defense, naturally contribute to an overall homeostatic failure underlying neurodegeneration. In this chapter we shall deliver a brief on astroglial contribution to common neurodegenerative disorders and then continue with a detailed account on the pathological potential of astroglia in Alzheimer’s disease. Astrocytes undergo complex alterations in Alzheimer’s disease, which are represented by region-specific atrophy and asthenia at the early stages and reactivity at the late stages of the disease. These complex changes can be considered as pathologically relevant because they may define the early cognitive deficits and the later neurotoxicity in Alzheimer’s disease. Targeting astroglia in neurodegeneration may result in new therapeutic strategies aimed at preventing and delaying the progression of Alzheimer’s disease.
    Pathological Potential of Neuroglia. Possible New Targets for Medical Intervention, Edited by Alexei Verkhratsky, Vladimir Parpura, 09/2014: chapter Neurodegeneration and Neuroglia: Emphasis on Astroglia in Alzheimer’s Disease: pages 265 - 292; Springer., ISBN: 978-1-4939-0973-5
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