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Hippo/YAP Pathway Plays a Critical Role in Effect of GDNF Against Aβ-Induced Inflammation in Microglial Cells
Jie Qing1,2, Xiaoheng Liu2, Quan Wu1
1State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Abstract:
Neuroinflammation is a critical mechanism responsible for the progression of Alzheimer's disease (AD). Recent studies reveal that Hippo/Yes-associated protein (YAP) signaling pathway is highly associated with a series of inflammation-related disorders. Glial cell line-derived neurotrophic factor (GDNF), with its neurotrophic and anti-apoptotic functions for nervous system, has been demonstrated to decrease the expression of proinflammatory mediators. Here we investigated whether Hippo/YAP signaling may affect amyloid-β (Aβ)-induced proinflammatory cytokine production in microglial cells and explored its relationship with the anti-inflammation function of GDNF. The results showed that Aβ induced a decrease in the expression of YAP in microglia cells. YAP agonist XMU-MP-1 or its overexpression in microglial cells caused decreased expression of proinflammatory cytokines, whereas YAP antagonist Verteporfin or knockdown of YAP had the opposite effect. Treatment with GDNF resulted in upregulation of YAP expression and reduced the production of proinflammatory cytokines. Meanwhile YAP knockdown weakened the function of GDNF in microglial cells. In conclusion, Hippo/YAP pathway plays a critical role in effect of GDNF against Aβ-induced inflammatory response in microglia. Targeting GDNF or Hippo/YAP signaling may be promising therapeutic approach for the treatment of AD.
Insights
Glial cell line-derived neurotrophic factor (GDNF) reduces Alzheimer's disease inflammation by activating the Hippo/Yes-associated protein (YAP) pathway in microglia. Targeting GDNF or YAP may offer new treatments for Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neuroinflammation drives Alzheimer's disease (AD) progression.
- The Hippo/Yes-associated protein (YAP) pathway is linked to inflammation.
- Glial cell line-derived neurotrophic factor (GDNF) has anti-inflammatory properties.
Purpose of the Study:
- Investigate if Hippo/YAP signaling influences amyloid-β (Aβ)-induced inflammation in microglia.
- Explore the relationship between GDNF's anti-inflammatory effects and the Hippo/YAP pathway.
Main Methods:
- Examined YAP expression in microglia exposed to Aβ.
- Utilized YAP activators (XMU-MP-1, overexpression) and inhibitors (Verteporfin, knockdown).
- Assessed the impact of GDNF treatment on YAP expression and cytokine production, with and without YAP knockdown.
Main Results:
- Aβ decreased YAP expression in microglia.
- Activating YAP reduced pro-inflammatory cytokines; inhibiting YAP increased them.
- GDNF upregulated YAP and decreased pro-inflammatory cytokines.
- YAP knockdown diminished GDNF's anti-inflammatory effect.
Conclusions:
- The Hippo/YAP pathway is crucial for GDNF's anti-inflammatory action against Aβ-induced responses in microglia.
- Targeting GDNF or the Hippo/YAP pathway presents a potential therapeutic strategy for AD.
