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Published on: November 9, 2018
PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in Alzheimer's
Ying Du1, Tiantian Guo2, Yunfeng Hao1
1Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Introduction:
To investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD).
Methods:
We analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia-mediated neuroinflammation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, RNA sequencing (RNA-seq), and immunofluorescence staining.
Results:
PKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aβ) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF-κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aβ-induced microglial responses and improved cognitive function in an AD mouse model.
Discussion:
Our study identifies PKCδ as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.
Highlights:
Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aβ) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF-κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aβ-enhanced NF-κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.
Insights
Protein kinase C delta (PKCδ) is elevated in Alzheimer's disease (AD) patients and drives neuroinflammation by activating microglia. Inhibiting PKCδ reduces inflammation and improves cognition in AD mouse models, identifying it as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by neuroinflammation.
- Microglia play a central role in AD-associated neuroinflammation.
- The specific role of protein kinase C delta (PKCδ) in AD neuroinflammation requires further elucidation.
Purpose of the Study:
- To investigate the role of protein kinase C delta (PKCδ) in microglia-mediated neuroinflammation in Alzheimer's disease (AD).
- To assess PKCδ as a potential biomarker and therapeutic target for AD.
Main Methods:
- Analysis of PKCδ and inflammatory cytokine levels in cerebrospinal fluid (CSF) of AD patients and controls.
- Evaluation of cellular expression patterns of PKCδ using immunofluorescence staining.
- Assessment of PKCδ modulation effects on microglia-mediated neuroinflammation via qRT-PCR, western blot, and RNA-seq.
- In vivo studies using an AD mouse model to evaluate the therapeutic potential of PKCδ inhibition.
Main Results:
- PKCδ levels were significantly increased in the CSF of AD patients and correlated positively with inflammatory cytokines.
- PKCδ is primarily expressed in microglia and its expression/secretion is upregulated by amyloid beta (Aβ) stimulation.
- Aβ-induced PKCδ activation led to NF-κB pathway upregulation and increased pro-inflammatory cytokine production.
- Downregulation or inhibition of PKCδ attenuated Aβ-induced microglial responses and improved cognitive function in an AD mouse model.
Conclusions:
- PKCδ is implicated in the pathogenesis of microglia-mediated neuroinflammation in Alzheimer's disease.
- PKCδ represents a promising therapeutic target for mitigating neuroinflammation in AD.
- PKCδ may serve as a valuable biomarker for AD diagnosis and progression.
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