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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on
Shao Qin Tiong1, Raxshanaa N Mohgan1, Jia Yee Quek1
1School of Pharmacy, IMU University, Bukit Jalil, Kuala Lumpur, Malaysia.
Abstract:
Background: Abnormal elevation of transforming growth factor-beta (TGF-β) has been observed among Alzheimer's disease (AD) patients. This may be due to microglia-mediated release of proinflammatory cytokines, which promote neuroinflammation and neuronal apoptosis. Silencing of TGFBR1, a gene encoding TGF-β receptor type I (TGF-βR1), has resulted in neuronal survival from amyloid-beta (Aβ)-induced neurotoxicity. Therefore, the present study investigated the neuroprotective effect of TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Methods: The neuroprotective effect of TGF-βR1 inhibitors against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation were investigated using the RealTime-Glo™ MT Cell Viability Assay. The inhibitory effect of TGF-βR1 inhibitors on Aβ-induced microglia-mediated production of proinflammatory cytokines (TNF-α and IL-1β) was determined using enzyme-linked immunosorbent assay (ELISA). Results: TGF-βR1 inhibitors (RepSox, Galunisertib, and Vactosertib) at the tested concentrations (6.25-150 nM) showed no significant cytotoxicity effects on SH-SY5Y and BV-2 cells. Moreover, treatments with these inhibitors exhibited neuroprotection on SH-SY5Y cells against Aβ-induced direct neurotoxicity. The trend of cell viability after 24 h treatment also supports the microscopic images of the cells' morphology. Furthermore, pretreatment with these inhibitors conferred indirect neuroprotective effect against Aβ-induced microglia-mediated neuroinflammation by attenuating the production of proinflammatory cytokines (TNF-α and IL-1β). Conclusion: The inhibition of the TGF-β signaling pathway in neuronal and microglia cells by TGF-βR1 inhibitors resulted in neuroprotection against Aβ-induced direct neurotoxicity and microglia-mediated neuroinflammation. Hence, targeting the TGF-β signaling pathway in both neuronal and microglia cells could provide a promising therapeutic strategy in AD.
Insights
Transforming growth factor-beta receptor type I (TGF-βR1) inhibitors protect against Alzheimer's disease (AD) neurotoxicity and neuroinflammation. Targeting TGF-βR1 in neurons and microglia offers a promising therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Elevated transforming growth factor-beta (TGF-β) is linked to Alzheimer's disease (AD), potentially via microglia-induced neuroinflammation and apoptosis.
- Silencing the TGF-β receptor type I (TGFBR1) gene promotes neuronal survival against amyloid-beta (Aβ) neurotoxicity.
Purpose of the Study:
- To investigate the neuroprotective potential of TGF-βR1 inhibitors against Aβ-induced neurotoxicity and microglia-mediated neuroinflammation.
- To evaluate specific TGF-βR1 inhibitors: RepSox, Galunisertib, and Vactosertib.
Main Methods:
- Cell viability was assessed using the RealTime-Glo™ MT Cell Viability Assay.
- Proinflammatory cytokine production (TNF-α, IL-1β) was measured via ELISA.
- Neuroprotection was evaluated against direct Aβ toxicity and Aβ-induced microglia-mediated inflammation.
Main Results:
- TGF-βR1 inhibitors showed no cytotoxicity on SH-SY5Y (neuronal) and BV-2 (microglia) cells.
- Inhibitors provided neuroprotection against direct Aβ neurotoxicity and attenuated Aβ-induced release of TNF-α and IL-1β.
- Pretreatment with inhibitors offered indirect neuroprotection against microglia-mediated neuroinflammation.
Conclusions:
- Inhibiting the TGF-β signaling pathway via TGF-βR1 inhibitors confers neuroprotection in both neuronal and microglia cells.
- Targeting the TGF-β pathway in neurons and microglia presents a potential therapeutic strategy for Alzheimer's disease.
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