Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 286 - 286

Published: Feb. 5, 2024

The key to the effective treatment of neurodegenerative disorders is a thorough understanding their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment glymphatic system function in neurodegeneration contributes progression pathological question arises as how related. This review highlights direct indirect influence these two seemingly independent Protein aggregates, characteristic feature neurodegeneration, correlated with clearance neuroinflammation. Glial cells cannot be overlooked when considering neuroinflammatory Astrocytes essential for functioning play crucial role inflammatory responses central nervous system. It imperative acknowledge significance AQP4, protein that exhibits high degree polarization astrocytes AQP4 influences processes have not yet been clearly delineated. Another interesting issue gut–brain axis microbiome, which potentially impact discussed A discussion correlation between may contribute exploring pathomechanism neurodegeneration.

Language: Английский

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Modulation of glymphatic system by visual circuit activation alleviates memory impairment and apathy in a mouse model of Alzheimer’s disease

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Alzheimer's disease is characterized by progressive amyloid deposition and cognitive decline, yet the pathological mechanisms treatments remain elusive. Here we report therapeutic potential of low-intensity 40 hertz blue light exposure in a 5xFAD mouse model disease. Our findings reveal that treatment prevents memory decline 4-month-old mice motivation loss 14-month-old mice, accompanied restoration glial water channel aquaporin-4 polarity, improved brain drainage efficiency, reduction hippocampal lipid accumulation. We further demonstrate beneficial effects are mediated through activation vLGN/IGL-Re visual circuit. Notably, concomitant use anti-Aβ antibody with demonstrates soluble Aβ clearance performance mice. These offer functional evidence on Aβ-related pathologies suggest its as supplementary strategy to augment efficacy antibody-based therapy. Treatments for (AD) limited. Here, authors show activates circuit boost glymphatic drainage, enhances memory, motivation, therapy AD.

Language: Английский

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Astrocytes in selective vulnerability to neurodegenerative disease

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(4), P. 289 - 302

Published: March 22, 2024

Selective vulnerability of specific brain regions and cell populations is a hallmark neurodegenerative disorders. Mechanisms selective involve neuronal heterogeneity, functional specializations, differential sensitivities to stressors pathogenic factors. In this review we discuss the growing body literature suggesting that, like neurons, astrocytes are heterogeneous specialized, respond integrate diverse inputs, induce effects on function. disease, undergo specific, context-dependent changes that promote different trajectories outcomes. We propose contribute through maladaptive transitions context-divergent phenotypes impair functions. Further studies multifaceted roles in disease may provide new therapeutic approaches enhance resilience against

Language: Английский

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40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 6, 2024

Abstract The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of brain milieu since it defines cerebral spinal fluid flow in parenchyma and eliminates metabolic waste. Animal human studies have uncovered several important physiological factors regulating glymphatic including sleep, aquaporin-4, hemodynamic factors. Yet, our understanding modulation limited, which has hindered development glymphatic-based treatment aging neurodegenerative disorders. Here, we present evidence from fluorescence tracing, two-photon recording, dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced influx efflux independently anesthesia an effect attributed to increased astrocytic aquaporin-4 polarization vasomotion. Adenosine-A 2A receptor (A R) signaling emerged neurochemical underpinning flickering-induced enhancement flow, based on cerebrofluid adenosine levels, abolishment by pharmacological or genetic inactivation equilibrative nucleotide transporters-2 A R, physical functional R–aquaporin-4 interaction astrocytes. These findings establish a novel non-invasive strategy with translational potential relieve

Language: Английский

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Evidence that Alzheimer’s Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 99(2), P. 447 - 470

Published: April 23, 2024

Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized lines supporting this hypothesis highlighted similarities between Aβ anti-microbial peptides mediating cell/synapse competition. In cell competition, deploy multitude mechanisms ensure both self-protection competitor elimination. Here review recent studies showing similar are at play Aβ-mediated synapse competition perturbations these underpin Alzheimer’s disease (AD). Specifically, discuss ApoE, two crucial players AD, co-operate regulation Glial ApoE promotes by increasing production trophic monomeric inhibiting its assembly into toxic oligomers. Conversely, oligomers, once assembled, promote elimination synapses via direct activity amplification “eat-me” signals promoting weak synapses. further summarize neuronal may be part gene regulatory network normally plasticity, explaining selective vulnerability expressing neurons AD brains. Lastly, sleep key Aβ-orchestrated which not only induced but also required for underlining link AD. Together, results strongly argue gone awry, novel perspective research.

Language: Английский

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Higher intracranial arterial pulsatility is associated with presumed imaging markers of the glymphatic system: An explorative study

NeuroImage, Journal Year: 2024, Volume and Issue: 288, P. 120524 - 120524

Published: Jan. 24, 2024

Arterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation glymphatic clearance. However, whether intracranial arterial pulsatility associated with markers in humans not yet studied. Seventy-three community participants were enrolled study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify hemodynamic parameters including flow index (PIflow) and area (PIarea) from 13 major intracerebral segments. Three presumed neuroimaging system measured: dilation perivascular space (PVS), diffusivity along (ALPS), volume fraction free water (FW) white matter. We explored relationships between PIarea, PIflow, markers, controlling for related covariates. PIflow internal carotid artery (ICA) C2 segment (OR, 1.05; 95% CI, 1.01-1.10, per 0.01 increase PI) C4 1.01-1.09) positively basal ganglia PVS, ICA 1.06, 1.02-1.10) correlated PVS ALPS basilar (β, -0.273, p, 0.046) PIarea -0.239, 0.041) C7 segments -0.238, 0.037). Intracranial system, but results consistent across different markers. Further studies are warranted confirm these findings.

Language: Английский

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Glymphatic inhibition exacerbates tau propagation in an Alzheimer’s disease model

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 5, 2024

Abstract Background The aggregation and spread of misfolded amyloid structured proteins, such as tau α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer’s Parkinson’s disease. These proteins possess a prion-like property, enabling their transmission from cell to leading propagation throughout the central peripheral nervous systems. While mechanisms underlying intracellular still being elucidated, targeting extracellular space has emerged potential therapeutic approach. glymphatic system, brain-wide pathway responsible for clearing metabolic waste gained attention promising target removing these toxic proteins. Methods In this study, we investigated impact long-term modulation function on by chronically treating mouse model pharmacological inhibitor AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated into hippocampus overlying cortex, subsequently treated TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) 10-weeks. During time, animal memory was studied using cognitive behavioural tasks, structural MR images acquired brain in vivo prior extraction immunohistochemical characterisation. Results Our findings demonstrate increased transhemispheric following inhibition clearance. Moreover, disruption system aggravated recognition exacerbated regional changes volume detected model. When initiation drug treatment delayed several weeks post-inoculation, alterations attenuated. Conclusions results indicate that modulating AQP4 and, consequently, clearance, it is possible modify brain, particularly during initial stages highlight critical role preserving healthy homeostasis offer valuable insights implications managing diseases characterized protein spread.

Language: Английский

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Glymphatic fluid transport is suppressed by the aquaporin‐4 inhibitor AER‐271

Glia, Journal Year: 2024, Volume and Issue: 72(5), P. 982 - 998

Published: Feb. 16, 2024

Abstract The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial from along perivenous white matter tracts. This directional flow supports clearance of metabolic wastes produced by brain. Glymphatic transport is facilitated aquaporin‐4 (AQP4) water channels, which are enriched in astrocytic vascular endfeet comprising outer boundary space. Yet, prior studies AQP4 function have relied on genetic models, or correlated altered expression with disease states. Herein, we sought to pharmacologically manipulate inhibitor AER‐271 assess contribution mouse Administration inhibited influx as measured CSF tracer infused cisterna magna increases volume diffusion‐weighted MRI. Furthermore, efflux assessed an vivo assay. Importantly, did not affect localization endfeet, nor any effect deficient mice. Since acute pharmacological inhibition directly decreased wild‐type but mice, foresee a new tool for manipulation rodent

Language: Английский

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Photobiomodulation in experimental models of Alzheimer’s disease: state-of-the-art and translational perspectives

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 21, 2024

Abstract Alzheimer’s disease (AD) poses a significant public health problem, affecting millions of people across the world. Despite decades research into therapeutic strategies for AD, effective prevention or treatment this devastating disorder remains elusive. In review, we discuss potential photobiomodulation (PBM) preventing and alleviating AD-associated pathologies, with focus on biological mechanisms underlying therapy. Future directions guidance clinical practice non-invasive non-pharmacological therapy are also highlighted. The available evidence indicates that different paradigms, including transcranial systemic PBM, along recently proposed remote all could be promising AD. PBM exerts diverse effects, such as enhancing mitochondrial function, mitigating neuroinflammation caused by activated glial cells, increasing cerebral perfusion, improving glymphatic drainage, regulating gut microbiome, boosting myokine production, modulating immune system. We suggest may serve powerful intervention

Language: Английский

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The glymphatic system and Amyotrophic lateral sclerosis

Progress in Neurobiology, Journal Year: 2024, Volume and Issue: 234, P. 102571 - 102571

Published: Jan. 22, 2024

Language: Английский

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