CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer’s Disease

Zhang, Xiaofang; Zhao, Yan-feng; Zhu, Shunwei; Huang, Weijie; Luo, Yan; Chen, Qing-Ying; Ge, Lijia; R, Li; Wang, Jianfei; Sun, Mu; Xiao, Zhicheng; Fan, Guo-Huang

doi:10.3233/jad-150041

Cited by 23 publications

(25 citation statements)

References 51 publications

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“…Caspase-3 activity is increased by A cleaves tau into pro-aggregatory fragments that seed neurofibrillary pathology [74] and is closely linked with synaptic disruption in AD [52]. Direct application of CXCL1 to long-term cultured neurons led to caspase-3 activation, caspase-3 mediated tau cleavage, and tau mislocalisation into bead-like varicosities along neuronal processes [73], as found here. Given the strong links between tau mislocalisation and spine loss, our data strongly support further investigation of the CXCL1-CXCR2 interaction in rodent models of AD with both A and tau abnormalities to determine if this ligand-receptor pair is a novel target for therapeutic intervention.…”

Section: Discussionsupporting

confidence: 69%

“…Indeed, CXCL1 has previously been shown to induce tau phosphorylation via downstream effects on ERK1/2 and PI-3 kinase [56]. CXCL1 also promotes caspase-3 activation [73]. Caspase-3 activity is increased by A cleaves tau into pro-aggregatory fragments that seed neurofibrillary pathology [74] and is closely linked with synaptic disruption in AD [52].…”

Section: Discussionmentioning

confidence: 99%

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Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

Perez‐Nievas

Johnson

Beltran-Lobo

et al. 2021

Preprint

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Pathological interactions between beta-amyloid (Aβ) and tau drive the synapse loss that underlies neural circuit disruption and cognitive decline in Alzheimer's disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease. However, the contribution of astrocytes to Aβ-tau interactions in AD is not well understood. Here we stimulated mouse and human astrocytes with concentrations and species of human Aβ that mimic those in human AD brain. Astrocyte conditioned medium was collected and immunodepleted of Aβ before being added to rodent and human neuron cultures. Cytokines, identified in unbiased screens, were also applied to neurons, including following the pre-treatment of neurons with chemokine receptor antagonists. Tau mislocalisation, synaptic markers and dendritic spine numbers were measured in cultured neurons and organotypic brain slice cultures. Conditioned medium from astrocytes stimulated with Aβ induced tau mislocalisation and exaggerated synaptotoxicity that is recapitulated following spiking of neuron culture medium with recombinant C-X-C motif chemokine ligand-1 (CXCL1), a chemokine we show to be upregulated in Alzheimer's disease brain. Antagonism of neuronal C-X-C motof chemokine receptor 2 (CXCR2), prevented tau mislocalisation and synaptotoxicity in response to CXCL1 and Aβ-stimulated astrocyte secretions. Our data indicate that astrocytes exacerbate tau mislocalisation and the synaptotoxic effects of Aβ via interactions of astrovyctic CXCL1 and the neuronal CXCR2 receptor, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

Perez‐Nievas

Johnson

Beltran-Lobo

et al. 2021

Preprint

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“…Moreover, monocytes from AD patients produce significantly higher amounts of CXCL1 compared to age-matched controls, which causes these monocytes to migrate from the blood to the brain [41]. In the brain, CXCL1 also promotes the cleavage of tau, which is considered an early event in AD development [42]. Taken together, the literature findings on the relationship between AD and the brain levels of CCL3, CCL5 and CXCL1 are opposed to the negative concordance between AD and their blood levels that we found.…”

Section: Discussionmentioning

confidence: 99%

Shared Genetic Etiology between Alzheimer’s Disease and Blood Levels of Specific Cytokines and Growth Factors

Linden

Witte

Poelmans

2021

Genes

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Late-onset Alzheimer’s disease (AD) has a significant genetic and immunological component, but the molecular mechanisms through which genetic and immunity-related risk factors and their interplay contribute to AD pathogenesis are unclear. Therefore, we screened for genetic sharing between AD and the blood levels of a set of cytokines and growth factors to elucidate how the polygenic architecture of AD affects immune marker profiles. For this, we retrieved summary statistics from Finnish genome-wide association studies of AD and 41 immune marker blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 15 cytokines and growth factors, we identified genetic sharing with AD. We also found positive and negative genetic concordances—implying that genetic risk factors for AD are associated with higher and lower blood levels—for several immune markers and were able to relate some of these results to the literature. Our results imply that genetic risk factors for AD also affect specific immune marker levels, which may be leveraged to develop novel treatment strategies for AD.

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“…CXCR1/2 signaling is also implicated in various neurodegenerative diseases, such as Alzheimer's disease (AD) and stroke 197-201. Increased expression of CXCL8 in serum and brain of HIV-1 patients is associated with neurocognitive disorders 199.…”

Section: The Cxcl8-cxcr1/2 Axis In Inflammatory Diseasesmentioning

confidence: 99%

“…As a consequence, the activated neutrophils can cause ischemic injury to the tissue. Targeting CXCL8-CXCR1/2 axis has proved to be an effective approach to treat ischemic injury 203-205. Treatment with anti-CXCR2 antibody significantly blocked neutrophil infiltration into the infarcted area and reduced the size of infarction after long and delayed treatment in a mouse model of chronic myocardial infarction 206.…”

Section: The Cxcl8-cxcr1/2 Axis In Inflammatory Diseasesmentioning

confidence: 99%

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

Ha¹,

Debnath²,

Neamati³

2017

Theranostics

555

464

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The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

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CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer’s Disease

Cited by 23 publications

References 51 publications

Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

Shared Genetic Etiology between Alzheimer’s Disease and Blood Levels of Specific Cytokines and Growth Factors

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

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