Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Cell, Journal Year: 2022, Volume and Issue: 185(14), P. 2452 - 2468.e16

Published: June 13, 2022

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection found white-matter-selective in mice humans. Following mild mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused neurogenesis. Concordantly, humans lasting post-COVID exhibit levels. Compared SARS-CoV-2, influenza similar patterns reactivity, oligodendrocyte loss, at early time points, but after influenza, only pathology persisted. These findings illustrate neuropathophysiology cancer therapy may contribute to impairment following even COVID.

Language: Английский

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Function and therapeutic value of astrocytes in neurological diseases

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(5), P. 339 - 358

Published: Feb. 16, 2022

Language: Английский

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The neurobiology of long COVID

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3484 - 3496

Published: Oct. 7, 2022

Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 represent major component the post-acute syndrome, also known as long COVID. Here, we review what is understood about pathobiology impact on CNS discuss possible neurobiological underpinnings cognitive affecting survivors. We propose chief mechanisms that may contribute to this emerging health crisis.

Language: Английский

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Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease

Neuron, Journal Year: 2022, Volume and Issue: 110(11), P. 1788 - 1805.e10

Published: April 4, 2022

Language: Английский

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Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(7), P. 395 - 409

Published: June 12, 2023

Language: Английский

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Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

Language: Английский

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Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(6), P. 1420 - 1453

Published: Jan. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Language: Английский

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Astrocytes in human central nervous system diseases: a frontier for new therapies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Language: Английский

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

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 217, P. 102331 - 102331

Published: July 21, 2022

Language: Английский

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APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 154 - 161

Published: March 13, 2024

Abstract Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these are highly expressed glial cells 1 . However, the relationship between glia pathology remains poorly understood. Through single-nucleus RNA sequencing brain tissue disease, we have identified a microglial state defined by expression droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant patients having APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces expression, triglyceride synthesis droplet accumulation an APOE-dependent manner. Additionally, conditioned media from droplet-containing lead to Tau phosphorylation neurotoxicity Our findings suggest link neurotoxic microglia-derived factors, potentially providing therapeutic strategies disease.

Language: Английский

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