Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation.

Amyloid-beta (A beta) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial A beta 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 (5xFAD) mice, whose phagocytic efficiency for A beta was then impaired, and thereforePeli1depletion suppressed the A beta deposition in the brains of 5xFAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)beta, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBP beta and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBP beta 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.