Serum amyloid A drive microglia shift to a resolving phenotype through Nrf2.

Serum amyloid A (SAA) is an acute-phase protein that has been recognized as a diagnostic biomarker for several diseases. However, the functional studies about the effects of SAA on microglial activation seem controversial. Here, we discovered that SAA induces microglial cells polarize to a pro-resolving M2 phenotype by promoting the stability of the transcription factor Nrf2, which specifically regulates microglia towards a pro-resolving phenotype via metabolic reprogramming. Moreover, we identified that the AMPK/mTOR signaling pathway is involved in SAA-induced Nrf2 upregulation. Additionally, SAA protects cultured neuronal cells from MPP+-induced damage, and furthermore, local administration of SAA into the substantia nigra significantly attenuated MPTP-induced dopaminergic neuronal loss, thereby improving motor impairments in mice. In conclusion, for the first time we demonstrate SAA regulate microglial activation by promoting Nrf2 stabilization, ultimately protecting dopaminergic neurons and alleviating MPTP-induced PD-like pathology.