Distinct Neurotoxic Effects of Extracellular Tau Species in Primary Neuronal-Glial Cultures

Pampuščenko, Katryna; Morkūnienė, Ramunė; Krasauskas, Lukas; Smirnovas, Vytautas; Tomita, Taisuke; Borutaitė, Vilmantė

doi:10.1007/s12035-020-02150-7

Cited by 20 publications

(11 citation statements)

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“…Both tau and Ab accumulate in the brains of individuals affected by AD and other neurodegenerative diseases (Chi et al, 2018;Sebastia ´n-Serrano et al, 2018;Gallardo and Holtzman 2019). We have previously shown that tau and Ab induce neuronal loss in glial-neuronal cultures via microglial phagocytosis (Neher et al, 2011;Brelstaff et al, 2018;Pampuscenko et al, 2020Pampuscenko et al, , 2021, so we tested here whether this neuronal loss was mediated by P2Y 6 R. We found that the addition of extracellular tau protein (2N4R isoform) caused neuronal loss without inducing apoptosis or necrosis in mixed glial-neuronal cultures from WT mice (Figures 4A-4D). However, tau induced no significant neuronal loss in cultures from P2Y 6 R knockout (P2ry6 À/À ) mice (Figure 4C).…”

Section: Resultsmentioning

confidence: 97%

The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration

et al. 2021

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Section: Resultsmentioning

confidence: 97%

The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration

et al. 2021

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“…Once tau appears in the extracellular space, it may undergo endocytosis by surrounding cells and influence their functioning [34,35]. The results of the experiment of Pampuscenko et al [36] showed that the extracellular self-assembly dimers-tetramers of the 1N4R tau isoform (one extra exon in the N-terminal domain and four tubulin binding motifs), but not monomers, caused neuronal death in mixed neuronal/glial cell cultures. In contrast, monomeric and pre-aggregated tau peptide with 4R repeats but lacking the N-terminal fragment did not reduce the viability of the cells, suggesting that tau oligomers' neurotoxicity might be dependent on the presence of the N-terminal fragment in the molecule.…”

Section: Introductionmentioning

confidence: 99%

Tau Oligomers Neurotoxicity

Niewiadomska

Niewiadomski

Steczkowska

et al. 2021

Life

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Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer’s disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other’s aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system.

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“…The switch from a pro-resolution phenotype to a hypophagocytic phenotype was suggested to represent a proinflammatory state that occurs when the microglia fail to digest and degrade engulfed highly stable filamentous protein aggregates(58)(59)(60). Nevertheless, exposure of microglia to extracellular monomeric or small oligomeric 2N4R tau increases phagocytosis(4) although this result is conditionally dependent on tau isoform, concentration, and phosphorylation status(61). The molecular differences between the different states of the microglia under these different settings remain to be resolved.In addition to microglia being hypophagocytic, we show that coculture of microglia with P301S tau aggregate-containing neurons induced the hypofunctional microglia to secrete several senescence-associated factors (CXCL1, CXCL2, CCL5, IGFBP3, MMP9, and MMP3 (62)).…”

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Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

Brelstaff

Mason

Katsinelos

et al. 2021

Preprint

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The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

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Distinct Neurotoxic Effects of Extracellular Tau Species in Primary Neuronal-Glial Cultures

Cited by 20 publications

References 61 publications

The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration

The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration

Tau Oligomers Neurotoxicity

Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

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