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Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation
Jing Xu1, Tao Yu1, Enrica Caterina Pietronigro2
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Amyloid-β (Aβ) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial Aβ phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aβ was then impaired, and therefore Peli1 depletion suppressed the Aβ deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)β, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBPβ and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBPβ and the expression of CD36 and thus, promoted the phagocytic ability in microglial cells. Together, our findings established Peli1 as a critical regulator of microglial phagocytosis and highlighted the therapeutic potential by targeting Peli1 for the treatment of microglia-mediated neurological diseases.
Insights
Pellino 1 (Peli1) E3 ligase impairs microglial amyloid-β (Aβ) clearance in Alzheimer's disease models. Depleting Peli1 enhances microglial phagocytosis, reducing Aβ deposition and offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Amyloid-β (Aβ) accumulation is central to Alzheimer's disease (AD) pathology.
- Microglial phagocytosis of Aβ is crucial for disease progression but its regulation is unclear.
Purpose of the Study:
- To investigate the role of Pellino 1 (Peli1) in regulating microglial Aβ phagocytosis.
- To elucidate the molecular mechanisms by which Peli1 influences Aβ clearance.
Main Methods:
- Utilized five familial AD (5×FAD) mouse models to study Peli1 expression and Aβ deposition.
- Investigated the interaction between Peli1 and CCAAT/enhancer-binding protein (C/EBP)β.
- Analyzed the ubiquitination and degradation of C/EBPβ mediated by Peli1.
Main Results:
- Peli1 expression was elevated in microglia of 5×FAD mice, correlating with impaired Aβ phagocytosis.
- Peli1 depletion suppressed Aβ deposition in 5×FAD mouse brains.
- Peli1 directly ubiquitinated and degraded C/EBPβ, a transcription factor for scavenger receptor CD36.
- Loss of Peli1 increased C/EBPβ and CD36 levels, enhancing microglial phagocytic capacity.
Conclusions:
- Peli1 acts as a key regulator of microglial phagocytosis by targeting C/EBPβ.
- Targeting Peli1 presents a potential therapeutic strategy for Alzheimer's disease and other neurological disorders involving microglia.
