Blocking Microglial Proliferation by CSF-1R Inhibitor Does Not Alter the Neuroprotective Effects of Adoptive Regulatory T Cells in 3xTg Alzheimer's Disease Mice
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Published on: August 11, 2023
Seon-Young Park1, Nari Cha1, Soyoung Kim1
1Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
Abstract:
Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes cognitive impairment. Neuroinflammation induced by activated microglia exacerbates AD. Regulatory T cells (Tregs) play roles in limiting neuroinflammation by converting microglial polarization. Therefore, adoptive Treg therapy is considered an attractive option for neurodegenerative disorders. However, the mechanism underlying Treg therapy via microglial modulation is not fully understood. In this study, we sought to determine whether adoptively transferred Tregs were effective when microglia proliferation was inhibited by using GW2580, which is an inhibitor of CSF1R. We found that inhibition of microglial proliferation during Treg transfer did not alter the therapeutic effects of Tregs on cognitive deficits and the accumulation of Aβ and pTAU in 3xTg-AD mice. The expression of pro- and anti-inflammatory markers in the hippocampus of 3xTg mice showed that GW2580 did not affect the inhibition of neuroinflammation by Treg transfer. Additionally, adoptively transferred Tregs were commonly detected in the brain on day 7 after transfer and their levels decreased slowly over 100 days. Our findings suggest that adoptively transferred Tregs can survive longer than 100 days in the brain, suppressing microglial activation and thus alleviating AD pathology. The present study provides valuable evidence to support the prolonged efficacy of adoptive Treg therapy in AD.
Insights
Adoptive regulatory T cell (Treg) therapy effectively treats Alzheimer's disease (AD) pathology and cognitive deficits. Inhibiting microglial proliferation does not impact Treg therapy
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment.
- Neuroinflammation, driven by activated microglia, worsens AD progression.
- Regulatory T cells (Tregs) can mitigate neuroinflammation by modulating microglial polarization, making Treg therapy a promising approach for AD.
Purpose of the Study:
- To investigate the efficacy of adoptive Treg therapy in Alzheimer's disease (AD) models.
- To determine if inhibiting microglial proliferation affects Treg therapy outcomes.
- To elucidate the mechanism of Treg-mediated microglial modulation in AD.
Main Methods:
- Utilized 3xTg-AD mice, a model for Alzheimer's disease.
- Administered GW2580, a CSF1R inhibitor, to inhibit microglial proliferation.
- Performed adoptive transfer of regulatory T cells (Tregs).
- Assessed cognitive function, amyloid-beta (Aβ) and phosphorylated tau (pTAU) accumulation, and neuroinflammation markers.
Main Results:
- Inhibition of microglial proliferation did not alter the therapeutic effects of Treg transfer on cognitive deficits, Aβ, and pTAU.
- GW2580 did not interfere with Treg-mediated inhibition of neuroinflammation in the hippocampus.
- Adoptively transferred Tregs persisted in the brain for over 100 days, with levels decreasing slowly.
Conclusions:
- Adoptive Treg therapy demonstrates prolonged efficacy in alleviating Alzheimer's disease pathology.
- Tregs survive long-term in the brain, continuously suppressing microglial activation.
- These findings support the potential of Treg therapy as a sustained treatment for AD.
