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

Das, Rashmi Ranjan; Balmik, Abhishek Ankur; Chinnathambi, Subashchandrabose

doi:10.1186/s12974-019-1694-y

Cited by 84 publications

(65 citation statements)

References 88 publications

(103 reference statements)

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“…Of interest, oligomeric species of Tau play a vital role in propagation. This seeding effect of Tau is an early indication of Tauopathies and neurodegeneration, and it also has the potency to trigger activation of glia which gives rise to the inflammatory phase [12,[43][44][45]. The activation of microglia and its inflammatory cytokines again causes phosphorylation of Tau and increases its misfolding [38,[46][47][48][49].…”

Section: Neuroinflammation Mediated By Microgliamentioning

confidence: 99%

Role of dietary fatty acids in microglial polarization in Alzheimer’s disease

Desale

Chinnathambi

2020

J Neuroinflammation

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Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial cell phenotype and types of receptors on microglia. Reports suggest that dietary habits influence microglial polarization and the switching of microglial phenotype is very important in neurodegenerative diseases. Omega-3 fatty acids have more influence on the brain, and they are found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells. In Alzheimer's disease, one of the pathological proteins involved is Tau protein, and microtubuleassociated protein upon abnormal phosphorylation detaches from the microtubule and forms insoluble aggregates. Aggregated proteins have a tendency to propagate within the neurons and also become one of the causes of neuroinflammation. We hypothesize that tuning microglia towards anti-inflammatory phenotype would reduce the propagation of Tau in Alzheimer's disease.

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Section: Neuroinflammation Mediated By Microgliamentioning

confidence: 99%

Role of dietary fatty acids in microglial polarization in Alzheimer’s disease

Desale

Chinnathambi

2020

J Neuroinflammation

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“…These include scavenger receptors, toll-like receptors, transmembrane receptors such as integrin and Triggering receptor expressed on myeloid cells 2 reported to interact directly with amyloid-β fibrils for its activation, phagocytosis and internalization [ 35 , 65 , 66 ]. In AD, extracellular Tau species activates microglia via actin remodelling, promotes migration and phagocytosis of Tau for its clearance which could further be enhanced by other factors such as lipids and fatty acids [ 67 – 69 ]. In Tauopathy models, microglia are involved in Tau propagation, neuroinflammation and neuronal damage by the release of toxic factors and pro-inflammatory cytokines and also leads to synaptic losses [ 70 , 71 ].…”

Section: Microglia—scavengers Of Misfolded Proteinsmentioning

confidence: 99%

Interaction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation

2020

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Alzheimer’s disease (AD) is a neurodegenerative disease that leads to progressive loss of memory and dementia. The pathological hallmarks of AD include extracellular accumulation of amyloid-β peptides forming senile plaques and intracellular accumulation of Tau oligomers and filamentous species. Tau is a microtubule-binding protein that stabilizes tubulin to form microtubules under physiological condition. In AD/ pathological condition, Tau detaches from microtubules and aggregates to form oligomers of different sizes and filamentous species such as paired helical filaments. Microglia are the resident brain macrophages that are involved in the phagocytosis of microbes, cellular debris, misfolded and aggregated proteins. Chemokine receptor, CX3CR1 is mostly expressed on microglia and is involved in maintaining the microglia in a quiescent state by binding to its ligand, fractalkine (CX3CL1), which is expressed in neurons as both soluble or membrane-bound state. Hence, under physiological conditions, the CX3CR1/CX3CL1 axis plays a significant role in maintaining the central nervous system (CNS) homeostasis. Further, CX3CR1/CX3CL1 signalling is involved in the synthesis of anti-inflammatory cytokines and also has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation. In AD brain, the expression level of fractalkine is reduced, and hence Tau competes to interact with its receptor, CX3CR1. In microglia, phagocytosis and internalization of extracellular Tau species occurs in the presence of a chemokine receptor, CX3CR1 which binds directly to Tau and promotes its internalization. In this review, the pathophysiological roles of CX3CR1/fractalkine signalling in microglia and neurons at different stages of Alzheimer’s disease and the possible role of CX3CR1/Tau signalling has been widely discussed.

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“…( Gehrmann et al., 1995 , Sierra et al., 2013 ). Activated microglia also remodel membrane-associated actin network for active migration and effective phagocytosis of extracellular Tau oligomers ( Das et al., 2020 ). But the overactivation of microglia can lead to the engulfment of neuronal synapses, which results in memory loss and neurodegeneration in AD ( Hong et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Reduces GSK3β-Mediated Tau Phosphorylation, Enhances Nrf2 Nuclear Translocation and Anti-Inflammation

2020

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Alzheimer’s disease is a neuropathological condition with abnormal accumulation of extracellular Amyloid-β plaques and intracellular neurofibrillary tangles of Microtubule-associated protein Tau (Tau) in the brain. In pathological conditions, Tau undergoes post-translational modifications such as hyperphosphorylation by the activity of cellular kinases, which eventually leads to protein aggregation in neurons. Melatonin is a neuro-hormone that is mainly secreted from the pineal gland and functions to modulate the cellular kinases. In our study, we have checked the neuroprotective function of Melatonin by MTT and LDH assay, where Melatonin inhibited the Tau aggregates-mediated cytotoxicity and membrane leakage in Neuro2A cells. The potency of Melatonin has also been studied for the quenching of intracellular reactive oxygen species level by DCFDA assay and caspase 3 activity. Melatonin was shown to reduce the GSK3β mRNA and subsequent protein level as well as the phospho-Tau level (pThr181 and pThr212-pSer214) in okadaic acid-induced Neuro2A cells, as observed by western blot and immunofluorescence assay. Further, Melatonin has increased the cellular Nrf2 level and its nuclear translocation as an oxidative stress response in Tauopathy. The Melatonin was found to induce pro- and anti-inflammatory cytokines levels in N9 microglia. The mRNA level of cellular kinases such as as-GSK3β, MAPK were also studied by qRT-PCR assay in Tau-exposed N9 and Neuro2A cells. The immunomodulatory effect of Melatonin was evident as it induced IL-10 and TGF-β cytokine levels and activated MAP3K level in Tau-exposed microglia and neurons, respectively. Melatonin also downregulated the mRNA level of pro-inflammatory markers, IL-1β and Cyclooxygenase-2 in N9 microglia. Together, these findings suggest that Melatonin remediated the cytokine profile of Tau-exposed microglia, reduced Tau hyperphosphorylation by downregulating GSK3β level, and alleviated oxidative stress via Nrf2 nuclear translocation.

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

Cited by 84 publications

References 88 publications

Role of dietary fatty acids in microglial polarization in Alzheimer’s disease

Role of dietary fatty acids in microglial polarization in Alzheimer’s disease

Interaction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation

Melatonin Reduces GSK3β-Mediated Tau Phosphorylation, Enhances Nrf2 Nuclear Translocation and Anti-Inflammation

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