Felodipine attenuates neuroinflammatory responses and tau hyperphosphorylation through JNK/P38 signaling in tau-overexpressing AD mice
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Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Jeong-Woo Hwang1,2, Jeongha Kim1,2, Jin-Hee Park1
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41068, Republic of Korea.
Abstract:
We previously demonstrated that felodipine, an L-type calcium channel blocker, inhibits LPS-mediated neuroinflammatory responses in BV2 microglial cells and wild-type mice. However, the effects of felodipine on tau pathology, a hallmark of Alzheimer's disease (AD), have not been explored yet. Therefore, in the present study, we determined whether felodipine affects neuroinflammation and tau hyperphosphorylation in 3-month-old P301S transgenic mice (PS19), an early phase AD mice model for tauopathy. Felodipine administration decreased tauopathy-mediated microglial activation and NLRP3 expression in PS19 mice but had no effect on tauopathy-associated astrogliosis. In addition, felodipine treatment significantly reduced tau hyperphosphorylation at S202/Thr205 and Thr212/Ser214 residues via inhibiting JNK/P38 signaling in PS19 mice. Collectively, our results suggest that felodipine significantly ameliorates tau hyper-phosphorylation and tauopathy-associated neuroinflammatory responses in AD mice model for tauopathy and could be a novel therapeutic agent for AD.
Insights
Felodipine, an L-type calcium channel blocker, reduces neuroinflammation and tau hyperphosphorylation in an Alzheimer's disease mouse model. This suggests felodipine may be a potential therapeutic agent for Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Pharmacology
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by tau pathology and neuroinflammation.
- Felodipine, an L-type calcium channel blocker, previously showed anti-neuroinflammatory effects.
- The impact of felodipine on tau pathology in AD remains unexplored.
Purpose of the Study:
- To investigate the effects of felodipine on neuroinflammation and tau hyperphosphorylation in a mouse model of tauopathy.
- To evaluate felodipine's potential as a therapeutic agent for Alzheimer's disease.
Main Methods:
- Utilized P301S transgenic mice (PS19), an early-phase AD model for tauopathy.
- Administered felodipine to PS19 mice.
- Assessed microglial activation, NLRP3 expression, astrogliosis, and tau hyperphosphorylation.
- Analyzed the involvement of JNK/P38 signaling pathways.
Main Results:
- Felodipine decreased microglial activation and NLRP3 expression in PS19 mice.
- No significant effect of felodipine on tauopathy-associated astrogliosis was observed.
- Felodipine significantly reduced tau hyperphosphorylation at specific residues (S202/Thr205 and Thr212/Ser214).
- Inhibition of JNK/P38 signaling pathways was implicated in the reduction of tau hyperphosphorylation.
Conclusions:
- Felodipine ameliorates tau hyperphosphorylation and associated neuroinflammatory responses in an AD mouse model.
- Felodipine demonstrates potential as a novel therapeutic agent for Alzheimer's disease (AD).
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