FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression
1The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.
Neural Regeneration Research
|September 10, 2024
Summary
Researchers discovered that neurons express NLRP3, a protein involved in Alzheimer's disease progression. This neuronal NLRP3, regulated by FUBP3, directly impacts tau phosphorylation when amyloid-β is present, suggesting new therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Alzheimer's disease (AD) pathology involves amyloid-β plaques and hyperphosphorylated tau tangles.
- The NLRP3 inflammasome, primarily in microglia, is implicated in AD pathogenesis.
- Previous hypotheses suggested microglial NLRP3 indirectly influences neuronal tau phosphorylation.
Purpose of the Study:
- To investigate the role of neuronal NLRP3 in Alzheimer's disease.
- To identify regulatory mechanisms of neuronal NLRP3 expression.
- To explore FUBP3 as a potential therapeutic target for AD.
Main Methods:
- Biochemical methods to map the NLRP3 promoter.
- In vitro studies using primary neurons and Neuro2A cells.
- In vivo studies in aged wild-type and AD mouse models.
- Transcriptome analysis.
Main Results:
- Neurons express NLRP3 both in vitro and in vivo.
- Neuronal NLRP3 directly regulates tau phosphorylation in the presence of amyloid-β.
- FUBP3 is identified as a transcription factor essential for neuronal NLRP3 expression and tau phosphorylation.
- FUBP3 expression is significantly increased in cortical neurons of aged and AD mice.
- FUBP3's role in stress-induced responses and neuron-mediated immune responses is suggested.
Conclusions:
- Neuronal NLRP3, regulated by FUBP3, plays a direct role in the amyloid-β-induced tau phosphorylation cascade.
- Amyloid-β fundamentally alters NLRP3 expression regulation in neurons.
- FUBP3 is a promising therapeutic target for mitigating Alzheimer's disease progression.
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