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Published on: September 28, 2019
AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration
Shuai Liu1, Chunjie Yang2, Ningjun Zhang3
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; Department of Pharmacy, Center for Membrane Receptor and Brain Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China.
Abstract:
Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as an AXL-binding compound that rapidly activates AXL/AKT signaling. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo. These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing.
Insights
Alzheimer's disease involves iron metabolism issues in microglia. The study found AXL receptor protects against Aβ-induced ferroptosis, with levothyroxine (L-T4) showing therapeutic potential.
Area of Science:
- Neuroscience
- Cell Biology
- Metabolic Pathways
Background:
- Dysregulated iron metabolism drives Alzheimer's disease (AD) progression.
- Microglia, key iron regulators in the brain, are vulnerable to ferroptosis, exacerbating neurotoxicity.
- The role of microglial receptors in ferroptosis susceptibility is unclear.
Purpose of the Study:
- To investigate the role of plaque-associated receptors in microglial ferroptosis.
- To identify novel therapeutic targets for AD by understanding microglial metabolic vulnerabilities.
Main Methods:
- Identified AXL as a receptor tyrosine kinase crucial for microglial metabolic homeostasis.
- Utilized surface plasmon resonance imaging (SPRi) for drug screening.
- Investigated the effects of AXL modulation on Aβ-induced ferroptosis in microglia.
- Evaluated levothyroxine (L-T4) efficacy in AD models.
Main Results:
- AXL acts as a metabolic safeguard in microglia, protecting against Aβ-induced ferroptosis.
- Oligomeric Aβ (oAβ) exposure downregulates AXL, impairing glucose uptake and ATP production, increasing ferroptosis risk.
- Levothyroxine (L-T4), an FDA-approved drug, was identified as an AXL agonist.
- L-T4 treatment restored microglial homeostasis, inhibited ferroptosis, and improved neuropathology in vivo.
Conclusions:
- AXL is a critical metabolic safeguard in microglia against Aβ-induced ferroptosis.
- Levothyroxine (L-T4) demonstrates therapeutic potential for Alzheimer's disease by targeting microglial ferroptosis via AXL agonism.
- Drug repurposing of L-T4 offers a promising strategy for AD and other ferroptosis-related disorders.
