Reactive astrocytes in Alzheimer’s disease: A double-edged sword

Chun, Hyunaee; Lee, C. Justin

doi:10.1016/j.neures.2017.11.012

Cited by 143 publications

(141 citation statements)

References 96 publications

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“…Reactive gliosis is one of the hallmarks of AD pathology. Activated astrocytes and microglia improve uptake and degradation of Aβ . Nevertheless, sustained activation of glial cells is a primary source of neuroinflammation, which exacerbates neurodegenerative progression .…”

Section: Resultsmentioning

confidence: 99%

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

et al. 2018

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The imbalance between production and clearance of amyloid-beta (Aβ) is a key step in the onset and development of Alzheimer's disease (AD). Therefore, reducing Aβ accumulation in the brain is a promising therapeutic strategy for AD. The recently discovered glymphatic system and meningeal lymphatic vasculature have been shown to be critical for the elimination of interstitial waste products, especially Aβ, from the brain. In the present study, ligation of deep cervical lymph nodes was performed to block drainage of this system and explore the consequences on Aβ-related pathophysiology. Five-month-old APP/PS1 mice and their wild-type littermates received deep cervical lymphatic node ligation. One month later, behavioral testing and pathological analysis were conducted. Results demonstrated that ligation of dcLNs exacerbated AD-like phenotypes of APP/PS1 mice, showing more severe brain Aβ accumulation, neuroinflammation, synaptic protein loss, impaired polarization of aquaporin-4 and deficits in cognitive and exploratory behaviors. These results suggest that brain lymphatic clearance malfunction is one of the deteriorating factors in the progression of AD, and restoring its function is a potential therapeutic target against AD.

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Section: Resultsmentioning

confidence: 99%

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

et al. 2018

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“…It is beyond the scope of this review to list all their described functional changes and contributions to specific diseases. Readers are referred to recent reviews on astrocytes in HD (Khakh et al, ), AD (Chun & Lee, ; Osborn, Kamphuis, Wadman, & Hol, ; Perez‐Nievas & Serrano‐Pozo, ), MS (Wheeler & Quintana, ), SCI (Adams & Gallo, ; Sofroniew, ), TBI (Burda, Bernstein, & Sofroniew, ), stroke (Pekny et al, ), and epilepsy (Coulter & Steinhauser, ; Robel & Sontheimer, ). In general, deficits in normal astrocyte functions are reported and the existence of “killer astrocytes” releasing toxic molecule(s) was even proposed in amyotrophic lateral sclerosis [ALS, (Haidet‐Phillips et al, ; Nagai et al, )] and other neurodegenerative diseases [(Liddelow et al, ), see Section 5].…”

Section: Do Reactive Astrocytes Do Good Things?mentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

220

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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“…In the Alzheimer disease model, we have reported that an aberrant GABA synthesis and release in reactive astrocytes causes memory impairment and proposed that a similar mechanism should be involved in other brain diseases where reactive astrocytes are present including Parkinson's disease, stroke, and epilepsy (Jo et al, ; Sofroniew, ). We have recently demonstrated that the aberrant GABA in hippocampal astrocytes can be a useful molecular marker for reactive astrocytes (Chun & Lee, ). Despite these findings, the role of astrocytic GABA‐mediated tonic inhibition in epileptic seizures has not been tested yet.…”

Section: Introductionmentioning

confidence: 99%

Bestrophin1‐mediated tonic GABA release from reactive astrocytes prevents the development of seizure‐prone network in kainate‐injected hippocampi

Pandit

Neupane

Woo

et al. 2019

Glia

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Tonic extrasynaptic GABAA receptor (GABAAR) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA‐permeable Bestrophin‐1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)‐induced epileptic mice. Astrocyte‐specific Best1 over‐expression in KA‐injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi, serving as a good therapeutic target against altered E/I balance in epileptic seizures.

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Reactive astrocytes in Alzheimer’s disease: A double-edged sword

Cited by 143 publications

References 96 publications

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

Questions and (some) answers on reactive astrocytes

Bestrophin1‐mediated tonic GABA release from reactive astrocytes prevents the development of seizure‐prone network in kainate‐injected hippocampi

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