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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE236024 | GEO | 2023/10/04

REPOSITORIES: GEO

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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

Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration via apoE-dependent and independent mechanisms

Project description:APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here we show that overexpressing a low-density lipoprotein receptor (LDLR) transgene in P301S tau transgenic mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. ApoE specifically interacts with a high-molecular-weight tau species, and highly correlates with phospho-tau and insoluble tau levels. Microglial expression of the LDLR transgene reduces intracellular apoE and is associated with less microglial activation. snRNA-seq analysis of apoE-deficient or LDLR-overexpressing brains reveals that apoE deficiency drives microglial catabolism and increases the oligodendrocyte progenitor cell population. LDLR overexpression shares overlapping mechanisms, but uniquely upregulates microglial expression of specific ion channels and neurotransmitter receptors in tauopathy. A subset of disease-associated astrocytes with both neuroprotective and neurotoxic gene signatures is also identified.

2021-02-06 | GSE166261 | GEO

Leading edge airway epithelial cell responses to in vitro wounding

Project description:The airway epithelium of asthmatics is characterized by intrinsically abnormal wound repair that may contribute to disease pathobiology. In this study, we show that in asthma, the airway epithelial cells at the leading edge of a wound display aberrant migration patterns, reduced expression of α5 and β1 integrin subunits at baseline and during wound repair, resulting in dysregulated cell migration and an inability to fully repair. Transcriptional profiling identified the PI3K/Akt signaling pathway as the top upstream transcriptional regulator of integrin α5β1. Significantly, activation of Akt signaling enhanced airway epithelial repair in cultures derived from asthmatic children via upregulation of α5 and β1 integrin subunits. Conversely, inhibition of the PI3K/Akt signaling pathway in airway epithelial cultures from non-asthmatic children attenuated epithelial repair and reduced α5 and β1 integrin expression. Importantly, the FDA-approved drug celecoxib, and its non-COX2 inhibitory analogue dimethyl-celecoxib, also stimulated the PI3K/Akt/integrin α5β1 axis and restored airway epithelial repair in cells from asthmatics. Thus, targeting the PI3K/Akt pathway may represent a novel therapeutic avenue for asthma.

2020-03-25 | GSE117489 | GEO

E-cadherin loss induces autocrine activation of oncogenic growth factor signalling in metastatic lobular breast cancer.

Project description:Background: Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular breast cancer (ILC), no targeted therapy is available to treat this major breast cancer subtype. This study is aimed at identifying clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Methods: Reverse-phase protein array (RPPA) analyses were performed in the context of E-cadherin loss using mouse and human breast cancer cells. A combination of mRNA sequencing, conditioned medium growth assays and CRISPR-Cas9 knock-out experiments were performed to identify and validate activation of oncogenic pathways in ILC. Human ILC samples were employed to validate activation by immunohistochemistry on tissue micro-arrays. Finally, we assessed the effect of pathway inhibition using anoikis resistance and anchorage-dependent growth in vitro. Results: We demonstrate that E-cadherin loss leads to increased activation of FAK and PI3K/AKT signalling. Autocrine activation of growth factor receptor signalling and its downstream PI3K/AKT hub was a direct consequence of E-cadherin loss, independent of activating mutations in either PIK3CA, AKT or PTEN. Analysis of human ILC samples confirmed pathway activity, and pharmacological inhibition of AKT using AZD5363 and MK2206 resulted in robust inhibition of cell growth and survival of ILC cells in anchorage-dependent and independent conditions. Moreover, our results indicate a role for intracellular FAK in the regulation of ILC anoikis resistance. Conclusion: Our data demonstrate that E-cadherin loss evokes additional PI3K/AKT activation independent of oncogenic mutations in this pathway. We propose clinical intervention of PI3K/AKT in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.

2019-03-22 | GSE81977 | GEO

RNA sequencing in ovarian cancer cell line HEYA8 in terms of ECM1 silencing and reintroduction of ECM1 subtypes ECM1a and ECM1b

Project description:Extracellular Matrix Protein-1 (ECM1) promotes tumorigenesis in multiple organs, but the mechanisms associated with the functions and putative receptors of ECM1 subtypes have yet to be systematically clarified. We found in this study that secretory ECM1a functions as an oncoprotein to induce tumorigenesis through binding of the Gly-Pro-Arg (GPR) motif to integrin aXb2 and activation of AKT/FAK/Rho/cytoskeletal signaling. Nonsecretory ECM1b binds to myosin to block myosin phosphorylation, thus preventing cytoskeletal signaling activation and tumorigenesis. Based on RNA sequencing, we further found that the heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) protein induced by ECM1a favors the alternative mRNA splicing of ECM1a to control ECM1-associated signaling and tumorigenesis. ATP binding cassette subfamily G member 1 (ABCG1) transduces ECM1a-integrin aXb2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cisplatin resistance in cancer cells through upregulation of CD326-mediated cell stemness.

2021-05-27 | GSE171425 | GEO

Zeugodacus tau

Project description:Zeugodacus tau overview

| PRJNA492538 | ENA

Tinagl1 Suppresses Triple-negative Breast Cancer Progression by Simultaneously Targeting Integrin/FAK and EGFR Signaling Pathways

Project description:Enforced Tinagl1 expression in lung metastatic MDA-MB231 subline LM2 cells suppresses lung metastasis by inhibiting EGFR and Integrin/FAK activation

2018-12-31 | GSE99507 | GEO

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]

Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.

2022-03-10 | GSE198014 | GEO

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [bulk RNA-Seq]

2022-03-10 | GSE198013 | GEO

Zeugodacus tau

Project description:Zeugodacus tau Raw sequence reads

| PRJNA655252 | ENA