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PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau with inhibitors]

ABSTRACT: PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau with inhibitors]

PROVIDER: PRJNA992547 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25205205.fastq.gz	Fastqsanger.gz
	SRR25205206.fastq.gz	Fastqsanger.gz
	SRR25205207.fastq.gz	Fastqsanger.gz
	SRR25205208.fastq.gz	Fastqsanger.gz
	SRR25205209.fastq.gz	Fastqsanger.gz

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PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau with inhibitors]

Project description:Microtubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro- inflammatory state via integrin activation, causing them to release unknown neurotoxic factors. Here we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors. These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated astrogliosis and a target for anti-inflammation-based Alzheimer’s therapy.

2023-10-04 | GSE236866 | GEO

PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau vs OPN]

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PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis

Project description:PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis

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PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau vs OPN]

Project description:PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis [Tau vs OPN]

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PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-04 | GSE236868 | GEO

Zeugodacus tau

Project description:Zeugodacus tau overview

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Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex.

Project description:Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/β1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/β1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.

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Tau promotes neurodegeneration through global chromatin relaxation

Project description:We performed H3K9me2-based ChIP-seq to identify regions of the Drosophila genome that are H3K9me2-depleted due to transgenic neuronal expression of human mutant tau. Examination of H3K9me2 histone methylation in 10 day old control and tau transgenic Drosophila heads.

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Increased G3BP2-Tau interaction in Tauopathies is a natural defense against Tau aggregation

Project description:Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies.

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