Astrocyte molecular signatures in Huntington’s disease

Science Translational Medicine, Journal Year: 2019, Volume and Issue: 11(514)

Published: Oct. 16, 2019

Astrocyte gene expression is altered in mouse models of Huntington’s disease and postmortem brain samples from patients with HD.

Language: Английский

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The Role of Microglia and Astrocytes in Huntington’s Disease

Frontiers in Molecular Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: Oct. 25, 2019

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms cognitive decline. This review summarizes the contribution of microglia astrocytes to pathophysiology. Neuroinflammation in brain characterized by a reactive morphology these glial cells. Microglia are critical regulating neuronal activity maintaining optimal milieu for function. Previous studies provide evidence that activated contribute pathology through transcriptional activation pro-inflammatory genes perpetuate chronic inflammatory state. Reactive also display functional changes glutamate ion homeostasis energy metabolism. Astrocytic microglial may further death observed progression HD. Importantly, degree which neuroinflammatory detrimental neurons not well understood. Furthermore, recent observations compelling exert variety beneficial functions essential limiting tissue damage preserving function brain. Therefore, better understanding environment lead development targeted innovative therapeutic opportunities.

Language: Английский

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Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

Glia, Journal Year: 2017, Volume and Issue: 66(3), P. 637 - 653

Published: Nov. 27, 2017

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components intermediate filaments, is common feature in brains Alzheimer's patients. astrocytes are found close association with neuritic plaques; however, the precise role these glial cells disease pathogenesis unknown. In this study, using immunohistochemical techniques light electron microscopy, we report that plaque-associated reactive enwrap, engulf may digest presynaptic dystrophies hippocampus amyloid precursor protein/presenilin-1 (APP/PS1) mice. Microglia, brain phagocytic population, was apparently not engaged clearance. Phagocytic were present 35% 67% plaques at 6 12 months age, respectively. The proportion engulfed dystrophic neurites low, around 7% total both ages. This fact, along accumulation during course, suggests efficiency astrocyte might be limited or impaired. surrounding engulfing also detected patients confocal ultrastructural analysis. We posit activity contribute to clear dysfunctional synapses synaptic debris, thereby restoring impaired neural circuits reducing inflammatory impact damaged neuronal parts and/or limiting pathology. Therefore, potentiation properties represent potential therapy disease.

Language: Английский

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CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes

Neuron, Journal Year: 2020, Volume and Issue: 107(3), P. 436 - 453.e12

Published: June 1, 2020

Language: Английский

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Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(11), P. 2866 - 2884

Published: Oct. 9, 2023

Abstract Huntington’s disease (HD) is a devastating monogenic neurodegenerative characterized by early, selective pathology in the basal ganglia despite ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to development early cognitive phenotypes are poorly understood. Here we show that there loss synaptic connections between cortex striatum postmortem tissue from patients with HD associated increased activation localization complement proteins, innate immune molecules, elements. We also found levels secreted molecules elevated cerebrospinal fluid premanifest correlate established measures burden. In preclinical genetic models HD, proteins mediate elimination corticostriatal synapses at an stage pathogenesis, marking them for removal microglia, brain’s resident macrophage population. This process requires huntingtin be expressed both cortical striatal neurons. Inhibition complement-dependent mechanism through administration therapeutically relevant C1q function-blocking antibody or ablation receptor on microglia prevented synapse loss, excitatory input rescued visual discrimination learning flexibility deficits models. Together, our findings implicate cascade selective, presymptomatic HD; they provide new data support as therapeutic target intervention.

Language: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

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Drosophila glia: Few cell types and many conserved functions

Glia, Journal Year: 2018, Volume and Issue: 67(1), P. 5 - 26

Published: Nov. 15, 2018

Abstract Glial cells constitute without any dispute an essential element in providing efficiently operating nervous system. Work many labs over the last decades has demonstrated that neuronal function, from action potential generation to its propagation, eliciting synaptic responses subsequent postsynaptic integration, is evolutionarily highly conserved. Likewise, biology of glial appears conserved core elements and therefore, a deeper understanding expected benefit analyzing model organisms such as Drosophila melanogaster . particularly well suited for studying since fly system only limited number exists, which can be individually identified based on position set molecular markers. In combination with well‐known genetic tool box unprecedented level analysis feasible, not help identify novel molecules principles governing cell function but also will better understand functions first mammalian Here we review current knowledge glia spark interest using this analyze complex traits future.

Language: Английский

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An Optical Neuron-Astrocyte Proximity Assay at Synaptic Distance Scales

Neuron, Journal Year: 2018, Volume and Issue: 98(1), P. 49 - 66.e9

Published: April 1, 2018

Language: Английский

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Inter and Intracellular mitochondrial trafficking in health and disease

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 62, P. 101128 - 101128

Published: July 23, 2020

Language: Английский

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