Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity

Toral-Ríos, Danira; Patiño-López, Genaro; Gómez-Lira, Gisela; Gutiérrez, Rafael; Becerril-Pérez, Fernando; Rosales-Córdova, Aldebarán; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; León‐Rivera, Ismael; Soto‐Cruz, Isabel; Florán, Benjamí­n; Campos-Peña, Victoria

doi:10.3390/ijms21207458

Cited by 34 publications

(25 citation statements)

References 88 publications

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“…Reactive astrocytes can repair lesions and inhibit inflammation through the STAT3 signaling pathway, in contrast to the NF-κB signaling pathway [35]. However, in the Aβ-oligomer-induced AD model, STAT3 activation can mediate astrocyte activation, resulting in neurotoxicity [55]. Moreover, the STAT3 signaling pathway has also been shown to promote neuronal death, which is associated with epilepsy.…”

Section: Signal Transducer and Activator Of Transcription 3 (Stat3) Signaling Pathwaymentioning

confidence: 99%

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

Chen

Xue

Hölscher

2021

Acta Epileptologica

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Epilepsy is a common disease in the central nervous system. There is growing evidence that epilepsy is associated with glial cells, including astrocytes. Tumor necrosis factor α (TNFα) is a “master regulator” of proinflammatory cytokine production and is secreted by microglia and astrocytes. TNFα secreted by microglia can activate astrocytes. Additionally, TNFα can regulate neuron activity and induce epilepsy by increasing the glutamate release, reducing the expression of γ-aminobutyric acid, inducing neuroinflammation and affecting the synaptic function in astrocytes. This review summarizes the signaling pathways and receptors of TNFα acting on astrocytes that are related to epilepsy and provides insights into the potential therapeutic strategies of epilepsy for clinical practice.

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Section: Signal Transducer and Activator Of Transcription 3 (Stat3) Signaling Pathwaymentioning

confidence: 99%

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

Chen

Xue

Hölscher

2021

Acta Epileptologica

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“…Overall, OC-PF showed better activity than OC-SD, which may justify its superior potential for future use to control AD-associated amyloid pathology as a delivery system for OC. Progressive evidence supports the pivotal role of STAT3 as an upstream regulator of the pathogenesis of AD-related memory impairment [ 14 , 61 , 62 , 63 ]. STAT3 phosphorylation is also augmented by the complement C3 [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 phosphorylation is also augmented by the complement C3 [ 14 ]. On the other hand, STAT3 phosphorylation inhibition reduced the learning and memory impairments in 5xFAD mice [ 62 , 63 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

(-)-Oleocanthal Nutraceuticals for Alzheimer’s Disease Amyloid Pathology: Novel Oral Formulations, Therapeutic, and Molecular Insights in 5xFAD Transgenic Mice Model

et al. 2021

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Alzheimer’s disease (AD) is a complex progressive neurodegenerative disorder affecting humans mainly through the deposition of Aβ-amyloid (Aβ) fibrils and accumulation of neurofibrillary tangles in the brain. Currently available AD treatments only exhibit symptomatic relief but do not generally intervene with the amyloid and tau pathologies. The extra-virgin olive oil (EVOO) monophenolic secoiridoid S-(–)-oleocanthal (OC) showed anti-inflammatory activity through COX system inhibition with potency comparable to the standard non-steroidal anti-inflammatory drug (NSAID) like ibuprofen. OC also showed positive in vitro, in vivo, and clinical therapeutic effects against cardiovascular diseases, many malignancies, and AD. Due to its pungent, astringent, and irritant taste, OC should be formulated in acceptable dosage form before its oral use as a potential nutraceutical. The objective of this study is to develop new OC oral formulations, assess whether they maintained OC activity on the attenuation of β-amyloid pathology in a 5xFAD mouse model upon 4-month oral dosing use. Exploration of potential OC formulations underlying molecular mechanism is also within this study scope. OC powder formulation (OC-PF) and OC-solid dispersion formulation with erythritol (OC-SD) were prepared and characterized using FT-IR spectroscopy, powder X-ray diffraction, and scanning electron microscopy (SEM) analyses. Both formulations showed an improved OC dissolution profile. OC-PF and OC-SD improved memory deficits of 5xFAD mice in behavioral studies. OC-PF and OC-SD exhibited significant attenuation of the accumulation of Aβ plaques and tau phosphorylation in the brain of 5xFAD female mice. Both formulations markedly suppressed C3AR1 (complement component 3a receptor 1) activity by targeting the downstream marker STAT3. Collectively, these results demonstrate the potential for the application of OC-PF as a prospective nutraceutical or dietary supplement to control the progression of amyloid pathogenesis associated with AD.

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“…STAT3 is a signal transducer associated transcription factor and activation of STAT3 regulates reactive astrogliosis [34], induces GFAP [35] expression and production of pro-in ammatory factors such as TNFα and IL-6 [36,37]. These data suggest that STAT3 may play a crucial part in astrogliosis.…”

Section: Discussionmentioning

confidence: 99%

ChK1 Activation Induces Reactive Astrogliosis Through CIP2A/PP2A/STAT3 Pathway In Alzheimer's Disease

Zhou

Liu

et al. 2021

Preprint

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Background: In Alzheimer’s disease (AD), activation of astrocyte participates in the development of neurodegenerative diseases through neuroinflammation and disturbs glia-neuron interaction. Cancerous Inhibitor of PP2A (CIP2A) is an endogenous PP2A inhibitor. CIP2A upregulation specifically in astrocytes causes reactive astrogliosis, synaptic degeneration and cognitive deficits. However, the underlying mechanism of CIP2A upregulation remains unclear. Methods: In 3xTg-AD mice, we determined ChK1 was activated and related to DNA damage upregulating CIP2A by WB. We transfected EGFP-ChK1 plasmid into HEK293-T cell to determine ChK1 induces CIP2A upregulation and PP2A inhibition. We incubated Aβ and infected GFAP-ChK1-LV into primary astrocytes to confirm the signaling pathway in astrocytes and astrogliosis in AD. GFAP-ChK1-AAV was injected into C57/BL6 mice to induce specific expression of target protein in astrocytes. ChK1 inhibitor (SB) was performed to reverse the ChK1 activity. Outcomes were assessed using molecular (immunofluorescent staining, Western Blot and Golgi staining) measures to estimate symptomatic pathology and behavioral (NORT, OLT, MWM and FCT) measures to assess cognitive function. For most experiments, subjects were randomly assigned to experimental groups, and data were collected under blinded experimental conditions.Results: We demonstrated that DNA damage related Checkpoint kinase 1 (ChK1) was activated in 3xTg-AD mice. ChK1-mediated CIP2A overexpression drove inhibition of PP2A and activated STAT3, then led to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induced reactive astrogliosis, degeneration of neurons and deterioration of AD through CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 might be a potential therapeutic approach for AD treatment.Conclusions: These results suggest that ChK1 is upregulated in 3xTg-AD mice, ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis, neurodegeneration and AD-like cognitive deficits in vitro and in vivo.

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Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity

Cited by 34 publications

References 88 publications

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

The role of the TNFα-mediated astrocyte signaling pathway in epilepsy

(-)-Oleocanthal Nutraceuticals for Alzheimer’s Disease Amyloid Pathology: Novel Oral Formulations, Therapeutic, and Molecular Insights in 5xFAD Transgenic Mice Model

ChK1 Activation Induces Reactive Astrogliosis Through CIP2A/PP2A/STAT3 Pathway In Alzheimer's Disease

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