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Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity
Na Wang1, Lujian Cai1, Xinyu Pei1
1Center for Brain Sciences, First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
Abstract:
Apolipoprotein E (apoE) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit a substantial upregulation of apoE in AD-associated circumstances, despite astrocytes being the primary source of apoE expression and secretion in the brain. Although the role of astrocytic apoE in the brain has been extensively investigated, it remains unclear that whether and how apoE particles generated from astrocytes and microglia differ in biological characteristic and function. Here, we demonstrate the differences in size between apoE particles generated from microglia and astrocytes. Microglial apoE particles impair neurite growth and synapses, and promote neuronal senescence, whereas depletion of GPNMB (glycoprotein non-metastatic melanoma protein B) in microglial apoE particles mitigated these deleterious effects. In addition, human APOE4-expressing microglia are more neurotoxic than APOE3-bearing microglia. For the first time, these results offer concrete evidence that apoE particles produced by microglia are involved in neuronal senescence and toxicity.
Insights
Microglia-derived apolipoprotein E (apoE) particles worsen neuronal senescence and toxicity in Alzheimer's disease (AD). Depleting GPNMB in these particles reduces harmful effects, highlighting microglial apoE
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Apolipoprotein E (apoE) is implicated in Alzheimer's disease (AD) pathogenesis.
- Microglia upregulate apoE in AD, contrasting with astrocytes as the primary brain source.
- Differences in microglial vs. astrocytic apoE particle characteristics and functions are largely unknown.
Purpose of the Study:
- To investigate and compare the biological characteristics and functions of apoE particles from microglia and astrocytes.
- To elucidate the specific neurotoxic mechanisms of microglial apoE in AD.
Main Methods:
- Comparative analysis of apoE particle size generated from microglia and astrocytes.
- Assessment of microglial apoE particle effects on neurite growth, synapses, and neuronal senescence.
- Evaluation of GPNMB (glycoprotein non-metastatic melanoma protein B) depletion effects on microglial apoE toxicity.
- Comparison of neurotoxicity between human APOE4- and APOE3-expressing microglia.
Main Results:
- Demonstrated distinct size differences between microglial and astrocytic apoE particles.
- Microglial apoE particles were found to impair neurite growth, synaptic function, and promote neuronal senescence.
- Depletion of GPNMB in microglial apoE particles significantly mitigated these detrimental effects.
- Human APOE4-expressing microglia exhibited greater neurotoxicity compared to APOE3-expressing microglia.
Conclusions:
- Microglia-derived apoE particles possess unique properties contributing to neuronal senescence and toxicity.
- GPNMB plays a role in the neurotoxic effects of microglial apoE.
- These findings provide novel insights into the specific role of microglial apoE in AD neurodegeneration.
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