Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Фев. 26, 2024

Accumulating evidence highlights the involvement of astrocytes in Alzheimer's disease (AD) progression. We have previously demonstrated that human iPSC-derived ingest and modify synthetic tau fibrils a way enhances their seeding efficiency. However, differ significantly from vivo formed fibrils. To mimic situation brain, we here analyzed astrocytes' processing brain-derived its consequences for cellular physiology. Tau were extracted both AD control brains, aiming to examine any potential differences astrocyte response depending on origin Our results show internalize, but fail degrade, Instead, pathogenic, capable proteoforms are spread surrounding cells via tunneling nanotubes exocytosis. Notably, accumulation induces stronger reactive state astrocytes, compared fibrils, evident by augmented expression vimentin GFAP, as well an increased secretion pro-inflammatory cytokines IL-8 MCP-1. Moreover, conditioned media with fibril deposits induce synapse metabolic impairment neurons. Taken together, our data suggest more robust inflammatory neurotoxic phenotype accentuating nature important contributing factor inflammation neurodegeneration AD.

Язык: Английский

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Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Июнь 17, 2023

Tau deposits in astrocytes are frequently found Alzheimer's disease (AD) and other tauopathies. Since do not express tau, the inclusions have been suggested to be of neuronal origin. However, mechanisms behind their appearance relevance for progression remain unknown. Here we demonstrate, using a battery experimental techniques that human serve as an intermediator, promoting cell-to-cell spreading pathological tau. Human engulf process, but fail fully degrade dead neurons with tau pathology, well synthetic fibrils aggregates isolated from AD brain tissue. Instead, pathogenic is spread nearby cells via secretion tunneling nanotube mediated transfer. By performing co-culture experiments could show tau-containing induce pathology healthy directly. Furthermore, our results FRET based seeding assay, demonstrated proteoforms secreted by exceptional capacity, compared original species engulfed cells. Taken together, study establishes central role mediating which identifying novel treatment targets

Язык: Английский

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Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms

Molecular and Cellular Neuroscience, Год журнала: 2024, Номер 128, С. 103916 - 103916

Опубликована: Янв. 19, 2024

Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on progression still unclear. Our previous data show take up large amounts of aggregated amyloid-beta (Aβ) unable successfully degrade material, which instead stored intracellularly. The aim present study was analyze astrocytic Aβ deposits composition in detail order understand role propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived were exposed sonicated Aβ42 fibrils and magnetic beads. Live imaging immunocytochemistry confirmed ingested aggregates beads transported same lysosomal compartments perinuclear region, allowed us isolate from astrocytes. Using battery experimental techniques, mass spectrometry, western blot, ELISA electron microscopy we demonstrate truncate pack way makes them highly resistant. Moreover, release specifically truncated forms via different routes thereby expose neighboring cells pathogenic proteins. Taken together, our establishes for mediating pathology, could be relevance identifying novel treatment targets AD.

Язык: Английский

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Unveiling the Interplay: Neurovascular Coupling, Astrocytes and G Protein-Coupled Receptors in Alzheimer’s Disease

ACS Pharmacology & Translational Science, Год журнала: 2025, Номер 8(2), С. 271 - 285

Опубликована: Янв. 8, 2025

Astrocytes are a type of glial cell that involved in actively modulating synaptic plasticity, neurotransmitter homeostasis, and neuroinflammatory responses. More importantly, they coordinate neuronal activity cerebral blood flow (CBF) what is known as neurovascular coupling (NVC). NVC an essential mechanism maintains the high energy demand brain requires by supplying continuous rapid supply oxygen nutrients through CBF. Impairment one key events triggers spiral occurrences lead to clinical advancement Alzheimer's disease (AD). It yet be determined molecular manifestations impairment relate to; nonetheless, it believed alterations G protein-coupled receptors (GPCRs) responsible for exacerbating these effects. In this review, we summarize current evidence supporting involvement GPCRs on astrocytes pathophysiology AD. Additionally, propose potential research directions further elucidate underlying mechanisms evaluate feasibility targeting specific therapeutic strategy correct memory impairments associated with

Язык: Английский

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The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation

Neurology International, Год журнала: 2025, Номер 17(1), С. 6 - 6

Опубликована: Янв. 13, 2025

Neuroinflammation is a blanket term that describes the body’s complex inflammatory response in central nervous system (CNS). It encompasses phenotype shift to proinflammatory state, release of cytokines, recruitment peripheral immune cells, and wide variety other processes. has been implicated nearly every major CNS disease ranging from Alzheimer’s brain cancer. Understanding modeling neuroinflammation critical for identification novel therapeutic targets treatment diseases. Unfortunately, translation findings non-human models left much be desired. This review systematically discusses role human pluripotent stem cell (hPSC)-derived glia supporting cells within CNS, including astrocytes, microglia, oligodendrocyte precursor pericytes, endothelial describe state field hope future discoveries. hPSC-derived offer an expanded potential study pathobiology immunomodulatory cascades impact progression. While progress made development models, there explore application these understand CNS.

Язык: Английский

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A-beta-induced distress of astrocytes triggers Alzheimer disease pathology through non-canonical delta secretase activity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

ABSTRACT The importance of astrocytes for Alzheimer disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. In a genetic mouse model with diminished astrocyte stress response, even low levels amyloid-β trigger reactivity, resulting in brain inflammation and massive amyloid tau pathologies. This dysfunctional response to acts through activation δ secretase, stress-induced protease implicated both tau-related proteolytic processing. Our findings identify failed as an early inducer co-morbidity, noxious process AD acting unique non-canonical secretase pathway.

Язык: Английский

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Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Март 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Язык: Английский

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Organelle perturbation in Alzheimer’s disease: do intracellular amyloid-ß and the fragmented Golgi mediate early intracellular neurotoxicity?

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Апрель 15, 2025

Alzheimer’s disease is a devastating and incurable neurological disease. Most of the current research has focused on developing drugs to clear extracellular amyloid plaques in brain patients. However, this approach limited as it does not treat underlying cause In review, we highlight evidence field showing that accumulation intracellular toxic amyloid-ß could underpin very early events neuronal death both familial early-onset sporadic late-onset alzheimer’s Indeed, amyloid-ß, which produced within compartments, been shown perturb endosomal secretory organelles, different models, patients, leading membrane trafficking defects perturbation function associated with cognition defects. The Golgi apparatus central transport signaling hub at crossroads endocytic pathways ribbon structure hallmark Here, discuss role major player regulation amyloid-β production propose plays key cellular network can seed onset Moreover, an feedback loop enhanced level resulting before appearance clinical symptoms. Further advances defining molecular support design new therapeutic strategies target primary source toxicity

Язык: Английский

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Demystifying the Role of Neuroinflammatory Mediators as Biomarkers for Diagnosis, Prognosis, and Treatment of Alzheimer’s Disease: A Review

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(10), С. 2987 - 3003

Опубликована: Сен. 26, 2024

Neuroinflammatory mediators play a pivotal role in the pathogenesis of Alzheimer's Disease (AD), influencing its onset, progression, and severity. The precise mechanisms behind AD are still not fully understood, leading current treatments to focus mainly on managing symptoms rather than preventing or curing condition. amyloid tau hypotheses most widely accepted explanations for pathology; however, they do completely account neuronal degeneration observed AD. Growing evidence underscores crucial neuroinflammation pathology neuroinflammatory hypothesis presents promising new approach understanding driving This review examines importance biomarkers diagnosis, prognosis, treatment It delves into underlying AD, highlighting involvement various such as cytokines, chemokines, ROS. Additionally, this discusses potential diagnostic tools, prognostic indicators, therapeutic targets management. By intricate interplay between pathology, aims help development efficient plans fight debilitating neurological Furthermore, it elaborates recent advancements neuroimaging techniques biofluid analysis identification monitoring patients.

Язык: Английский

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Lipid–polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease

Journal of Materials Chemistry B, Год журнала: 2024, Номер 12(21), С. 5085 - 5097

Опубликована: Янв. 1, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in brain, increasing secretion proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD considered global health priority. The main limitations low drug bioavailability impermeability blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as promising field for development new nanosystems controlled targeted delivery drugs brain. Therefore, this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated transferrin (Tf) facilitate crossing BBB loaded

Язык: Английский

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