Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain

Kobayashi, Eiji; Nakano, Masako; Kubota, Kousuke; Himuro, Nobuaki; Mizoguchi, Shougo; Chikenji, Takako; Otani, Miho; Mizue, Yuka; Nagaishi, Kanna; Fujimiya, Mineko

doi:10.1038/s41598-018-19442-7

Cited by 85 publications

(84 citation statements)

References 62 publications

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“…These studies used AD patient samples and mouse models. In human patient samples, astrocytes are neuroprotective when glutamate transporters are highly expressed [47]. Glutamate transporter expression varies among mouse models of AD and depends on the brain region.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte senescence promotes glutamate toxicity in cortical neurons

et al. 2020

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Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo-or radiotherapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.

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Section: Discussionmentioning

confidence: 99%

Astrocyte senescence promotes glutamate toxicity in cortical neurons

et al. 2020

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“…This reduction of GLT-1/EAAT2 expression by astrocytes parallels the progression of AD pathology in the human brain (Simpson et al, 2010 ). Recently, it has been proposed that preservation of GLT-1/EAAT2 expression in GFAP+ reactive astrocytes could be a mechanism of resilience against AD neuropathological changes (Kobayashi et al, 2018 ). Other authors have shown a decreased solubility of GLT-1/EAAT2 in the brain of patients with AD, which could potentially impair the re-uptake of synaptic glutamate (Woltjer et al, 2010 ).…”

Section: Functional Consequences Of Astrocyte Reaction In Alzheimer’smentioning

confidence: 99%

Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Perez‐Nievas

Serrano-Pozo

2018

Front. Aging Neurosci.

227

221

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Reactive astrocytes were identified as a component of senile amyloid plaques in the cortex of Alzheimer’s disease (AD) patients several decades ago. However, their role in AD pathophysiology has remained elusive ever since, in part owing to the extrapolation of the literature from primary astrocyte cultures and acute brain injury models to a chronic neurodegenerative scenario. Recent accumulating evidence supports the idea that reactive astrocytes in AD acquire neurotoxic properties, likely due to both a gain of toxic function and a loss of their neurotrophic effects. However, the diversity and complexity of this glial cell is only beginning to be unveiled, anticipating that astrocyte reaction might be heterogeneous as well. Herein we review the evidence from mouse models of AD and human neuropathological studies and attempt to decipher the main conundrums that astrocytes pose to our understanding of AD development and progression. We discuss the morphological features that characterize astrocyte reaction in the AD brain, the consequences of astrocyte reaction for both astrocyte biology and AD pathological hallmarks, and the molecular pathways that have been implicated in this reaction.

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“…This reduction of GLT-1 expression in astrocytes results in increased glutamate levels at the synapse, which, by acting on eNMDAR, contributes to the progression of AD pathology in the human brain (Simpson et al, 2010). Additionally, a study performed in postmortem human samples suggests that the preservation of GLT-1 expression in reactive astrocytes could act as a neuroprotective mechanism against AD neuropathological changes (Kobayashi et al, 2018).…”

Section: The Old Man and The Alzheimer's Diseasementioning

confidence: 99%

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

Armada‐Moreira

Gomes

Pina

et al. 2020

Front. Cell. Neurosci.

182

128

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Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated

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Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain

Cited by 85 publications

References 62 publications

Astrocyte senescence promotes glutamate toxicity in cortical neurons

Astrocyte senescence promotes glutamate toxicity in cortical neurons

Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

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