A vicious cycle of β amyloid–dependent neuronal hyperactivation

Science, Год журнала: 2019, Номер 365(6453), С. 559 - 565

Опубликована: Авг. 8, 2019

Dissecting hyperactivation in AD Progressive accumulation of amyloid β (Aβ) the brain is a defining feature Alzheimer's disease (AD). At late stages AD, pathological Aβ accumulations cause neurodegeneration and cell death. However, neuronal dysfunction, consisting an excessively increased activity fraction neurons, already occurs early disease. Zott et al. explored cellular basis this hyperactivity mouse models (see Perspective by Selkoe). Aβ-mediated was linked to defect synaptic transmission exclusively active with most-active neurons having highest risk hyperactivation. Aβ-containing extracts from human patients sustained vicious cycle, underscoring potential relevance mechanism humans. Science , issue p. 559 ; see also 540

Язык: Английский

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Genetically Encoded Fluorescent Biosensors Illuminate the Spatiotemporal Regulation of Signaling Networks

Chemical Reviews, Год журнала: 2018, Номер 118(24), С. 11707 - 11794

Опубликована: Дек. 14, 2018

Cellular signaling networks are the foundation which determines fate and function of cells as they respond to various cues stimuli. The discovery fluorescent proteins over 25 years ago enabled development a diverse array genetically encodable biosensors that capable measuring spatiotemporal dynamics signal transduction pathways in live cells. In an effort encapsulate breadth have expanded, we endeavored assemble comprehensive list published engineered biosensors, discuss many molecular designs utilized their development. Then, review how high temporal spatial resolution afforded by has aided our understanding regulation at cellular subcellular level. Finally, highlight some emerging areas research both biosensor design applications on forefront

Язык: Английский

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Function and therapeutic value of astrocytes in neurological diseases

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(5), С. 339 - 358

Опубликована: Фев. 16, 2022

Язык: Английский

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Astrocyte Biomarkers in Alzheimer’s Disease

Trends in Molecular Medicine, Год журнала: 2019, Номер 25(2), С. 77 - 95

Опубликована: Янв. 2, 2019

Язык: Английский

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Deciphering the Astrocyte Reaction in Alzheimer’s Disease

Frontiers in Aging Neuroscience, Год журнала: 2018, Номер 10

Опубликована: Апрель 25, 2018

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

Язык: Английский

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Astroglial Glutamate Signaling and Uptake in the Hippocampus

Frontiers in Molecular Neuroscience, Год журнала: 2018, Номер 10

Опубликована: Янв. 17, 2018

Astrocytes have long been regarded as essentially unexcitable cells that do not contribute to active signaling and information processing in the brain. Contrary this classical view, it is now firmly established astrocytes can specifically respond glutamate released from neurons. Astrocyte initiated upon binding of ionotropic and/or metabotropic receptors, which result calcium signaling, a major form glial excitability. Release so-called gliotransmitters like glutamate, ATP D-serine response activation receptors has demonstrated modulate various aspects neuronal function hippocampus. In addition binds high-affinity, sodium-dependent transporters, results rapid buffering synaptically-released followed by its removal synaptic cleft through uptake into astrocytes. The degree control extracellular levels transporters depends on their expression ionic driving forces decrease with ongoing activity. Another determinant astrocytic could be precise morphological arrangement fine perisynaptic processes close synapses, defining diffusional distance for spatial proximity relation cleft. review, we will present an overview mechanisms physiological role glutamate-induced ion hippocampus mediated transporters. Moreover, discuss relevance astroglial homeostasis, focusing how activity-induced dynamic changes shape transmission at glutamatergic synapses.

Язык: Английский

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Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology

Nature Neuroscience, Год журнала: 2019, Номер 22(11), С. 1936 - 1944

Опубликована: Сен. 30, 2019

Язык: Английский

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Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: Integration of the glutamate/GABA-glutamine cycle

Progress in Neurobiology, Год журнала: 2022, Номер 217, С. 102331 - 102331

Опубликована: Июль 21, 2022

Язык: Английский

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Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease

Ageing Research Reviews, Год журнала: 2021, Номер 68, С. 101335 - 101335

Опубликована: Апрель 1, 2021

Astrocyte reactivity is a hallmark of neuroinflammation that arises with Alzheimer's disease (AD) and nearly every other neurodegenerative condition. While astrocytes certainly contribute to classic inflammatory processes (e.g. cytokine release, waste clearance, tissue repair), newly emerging technologies for measuring targeting cell specific activities in the brain have uncovered essential roles synapse function, metabolism, neurovascular coupling, sleep/wake patterns. In this review, we use holistic approach incorporate, expand upon, neuroinflammatory concepts consider how astrocyte dysfunction/reactivity modulates multiple pathological clinical hallmarks AD. Our ever-evolving understanding signaling neurodegeneration not only revealing new drug targets treatments dementia but suggesting reimagine AD pathophysiological mechanisms.

Язык: Английский

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Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Journal of Neurochemistry, Год журнала: 2023, Номер 166(2), С. 109 - 137

Опубликована: Март 15, 2023

Abstract Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these transmitters involves cell types working in close collaboration is facilitated by specialized cellular processes. Notably, are extensively recycled between neurons astrocytes a process known glutamate/GABA‐glutamine cycle, which essential maintain synaptic transmission. The cycle intimately coupled energy metabolism relies on metabolic both astrocytes. Importantly, display unique features allowing extensive metabolite release, hereby providing support for neurons. Furthermore, undergo complex adaptations response injury pathology, may greatly affect transmission during disease. In Milestone Review we outline major relation balancing signaling, including uptake, metabolism, recycling. We provide special focus how astrocyte contribute sustain neuronal through transfer. Recent advances reviewed context brain toxicity neurodegeneration. Finally, consider pathological serve potential target intervention. Integrating multitude fine‐tuned processes supporting neurotransmitter recycling, will aid next generation homeostasis. image

Язык: Английский

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