Living Neurons with Tau Filaments Aberrantly Expose Phosphatidylserine and Are Phagocytosed by Microglia

Brelstaff, Jack; Tolkovsky, Aviva M.; Ghetti, Bernardino; Goedert, Michel; Spillantini, Maria Grazia

doi:10.1016/j.celrep.2018.07.072

Cited by 137 publications

(167 citation statements)

References 51 publications

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“…The "arrow" has represented the migratory direction in front ends and the retraction of actin structures containing Iba1 from rear ends in N9 cells receptors and complement factors are also orchestrated for the recognition of death-associated signals and amplify the inflammatory burst to initiate improper phagocytosis of synapses [30,75]. Activated microglia engulf patho-proteins containing neurons flagging phosphatidylserine signals [76] and degrade via lysosomal machinery [58]. But, the failure of proper proteolysis can lead to the excretion of cleaved peptides, which acts as seed entities for further aggregation within healthy neurons [77].…”

Section: Discussionmentioning

confidence: 99%

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

Das

Balmik

Chinnathambi

2020

J Neuroinflammation

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Background: Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-β plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. Methods: In this study, we have prepared and stabilized hTau40 WT oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-β sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40 WT oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. Results: Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11 + Iba1 high microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. Conclusion: The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.

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Section: Discussionmentioning

confidence: 99%

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

Das

Balmik

Chinnathambi

2020

J Neuroinflammation

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“…Some of the consequences of these modifications are the impairment of axonal transport, as well as differential dendritic and post-synaptic tau distribution, among others [17]. Recently, new harmful roles have been associated with pathological tau, such as targeting microglia to promote neuron phagocytosis [18] or the impairment of nucleocytoplasmic transport, which would affect the integrity and functioning of the nucleus of the neurons [19].…”

Section: Introductionmentioning

confidence: 99%

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Regalado-Reyes

Furcila

Hernández

et al. 2019

JAD

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Despite extensive studies regarding tau phosphorylation progression in both human Alzheimer's disease cases and animal models, the molecular and structural changes responsible for neurofibrillary tangle development are still not well understood. Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI. Our results indicate that the AT100/pS396 ratio decreases in CA1 in accordance with the severity of the disease, along with its colocalization. We therefore propose the AT100/pS396 ratio as a new tool to analyze the tau pathology progression. Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer's disease.

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“…Phospholipids are a major component of cell membranes and phosphatidylserine has been proposed as a pro-apoptotic marker in pre-clinical neuronal models of tauopathies. [36,37] Sphingosine and its derivative sphingoamine, important components of sphingolipid metabolism, were also elevated in FTLD syndromes. Sphingosine derived lipids comprise up to one third of cell membranes and are highly prevalent in central nervous system white matter.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic changes associated with frontotemporal lobar degeneration syndromes

Murley

Jones

Gilchrist

et al. 2020

Preprint

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Objective: Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration. Methods: Plasma metabolomic profiles were measured from 134 patients with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n=30, non fluent variant primary progressive aphasia n=26, progressive supranuclear palsy n=45, corticobasal syndrome n=33) and 32 healthy controls. Results: Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration and controls with high accuracy (88.1-96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1-83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59-0.93], p=0.0018). Conclusions: The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

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Living Neurons with Tau Filaments Aberrantly Expose Phosphatidylserine and Are Phagocytosed by Microglia

Cited by 137 publications

References 51 publications

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Metabolomic changes associated with frontotemporal lobar degeneration syndromes

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