A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer's disease

Brawek, Bianca; Chesters, Robert; Klement, Daniel; Müller, Julia; Lerdkrai, Chommanad; Hermes, Marina; Garaschuk, Olga

doi:10.1016/j.neurobiolaging.2017.09.028

Cited by 29 publications

(24 citation statements)

References 44 publications

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“…GABA levels were inversely correlated with the distance to amyloid depositions, suggesting that both hypertrophy and GABA accumulation can be initiated by amyloid‐related processes . These results were corroborated by Brawek et al . who showed that in amyloid‐depositing mice, astrocytes accumulate around senile plaque, increased in soma size, and produce higher levels of GABA not only in DG but also in frontal cortex, suggesting that altered GABA production could be a general astrocyte dysfunction in AD.…”

Section: Pathological Significance Of Senescence In the Brainsupporting

confidence: 65%

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Spinelli

Martucciello

Nori

et al. 2018

Journal of Leukocyte Biology

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Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes throughout life is coming to light. The "senescence machinery" has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the beneficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases.

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Section: Pathological Significance Of Senescence In the Brainsupporting

confidence: 65%

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Spinelli

Martucciello

Nori

et al. 2018

Journal of Leukocyte Biology

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“…Morphologically, senescent-looking astrocytes have been characterized in the hippocampus and entorhinal cortex of 3xTg AD mice as astrocytes that are located far from amyloid plaques (>50 μm), with atrophied cell somas, and simplified processes (Olabarria et al, 2010 ; Yeh et al, 2011 ). However, other authors have reported that the size of astrocyte somas far from amyloid plaques (>60 μm) in an APP/PS1 transgenic mouse model is comparable to that of wild-type mice (Brawek et al, 2018 ). Another more dramatic morphological change that may resemble astrocyte senescence is the so-called clasmatodendrosis .…”

Section: Morphological Features Of Astrocyte Reaction In Alzheimer’s mentioning

confidence: 94%

Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Perez‐Nievas

Serrano-Pozo

2018

Front. Aging Neurosci.

225

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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“…However, study by Brawek et al (2018) challenged the aforementioned argument that tonic inhibition is a cause for the memory decline in AD [ 85 ]. In this recent study, they found a bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of AD.…”

Section: Reactive Astrocytes As a Potential Target For Alzheimer'smentioning

confidence: 99%

“…This argument agrees with previous study by Héja et al (2012) which showed that astrocytes are capable of converting neuronal hyperexcitability into tonic inhibition of the neighboring neurons via direct coupling between astrocytic glutamate uptake and GABA release from astrocytes [ 86 ]. Thus blocking this beneficial response of astrocytes would rather accelerate neural network dysfunction [ 85 ]. These conflicting arguments warrant further study to establish the exact role of astrocytic tonic inhibition on synaptic plasticity and Alzheimer's disease.…”

Section: Reactive Astrocytes As a Potential Target For Alzheimer'smentioning

confidence: 99%

Reactive Astrocytes as Drug Target in Alzheimer’s Disease

Assefa

Gebre

Altaye

2018

BioMed Research International

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Alzheimer's disease is a neurodegenerative disease characterized by deposition of extracellular amyloid-β, intracellular neurofibrillary tangles, and loss of cortical neurons. However, the mechanism underlying neurodegeneration in Alzheimer's disease (AD) remains to be explored. Many of the researches on AD have been primarily focused on neuronal changes. Current research, however, broadens to give emphasis on the importance of nonneuronal cells, such as astrocytes. Astrocytes play fundamental roles in several cerebral functions and their dysfunctions promote neurodegeneration and, eventually, retraction of neuronal synapses, which leads to cognitive deficits found in AD. Astrocytes become reactive as a result of deposition of Aβ, which in turn have detrimental consequences, including decreased glutamate uptake due to reduced expression of uptake transporters, altered energy metabolism, altered ion homeostasis (K+ and Ca+), increased tonic inhibition, and increased release of cytokines and inflammatory mediators. In this review, recent insights on the involvement of, tonic inhibition, astrocytic glutamate transporters and aquaporin in the pathogenesis of Alzheimer's disease are provided. Compounds which increase expression of GLT1 have showed efficacy for AD in preclinical studies. Tonic inhibition mediated by GABA could also be a promising target and drugs that block the GABA synthesizing enzyme, MAO-B, have shown efficacy. However, there are contradictory evidences on the role of AQP4 in AD.

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A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer's disease

Cited by 29 publications

References 44 publications

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Reactive Astrocytes as Drug Target in Alzheimer’s Disease

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