Abstract
Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads 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 induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1may be a potential therapeutic approach for AD treatment.
Highlights
In Alzheimer’s disease (AD), activation of astrocyte participates in the development of neurodegenerative diseases through neuroinflammation and disturbs glia-neuron interaction
These results suggest that Checkpoint kinase 1 (ChK1) is upregulated in 3xTg-Alzheimer's disease (AD) mice, ChK1-mediated Cancerous Inhibitor of Phosphatase 2A (PP2A) (CIP2A) overexpression drives inhibition of PP2A and activates Signal transducer and activator of transcription 3 (STAT3), leads to reactive astrogliosis, neurodegeneration and AD-like cognitive deficits in vitro and in vivo
DNA damage marker γH2A.X, active form of ChK1 (ChK1 phosphorylated at S345), and CIP2A levels were all increased in 3xTg-AD mouse brains (Fig. 1A, B)
Summary
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 in astrocytes causes reactive astrogliosis, synaptic degeneration and cognitive deficits. The underlying mechanism of CIP2A upregulation remains unclear. Alzheimer's disease (AD) is a common neurodegenerative disease with underlying mechanism unclarified. Glia in cell number are five to ten times of neurons, increasing body of studies have showed that abnormal activation of glia participated in the development of neurodegenerative diseases through neuroinflammation and disturbed glia-neuron interaction [3, 4]. Astrocyte as the major type of glia cell plays a crucial part in neurodegenerative diseases. The mechanisms underlying the activation of astrocytes in AD have not been completely understood
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