A Drug Screening Targeting Upregulation of Syk Gene Identifies Neochlorogenic Acid and L‐Arabinitol Capable of Inducing the M2 Phenotype of Microglia in Alzheimer's Disease

Despite numerous therapeutic attempts of Alzheimer's disease (AD), treatment options remain limited. Targeting microglia (MG) polarization from M1 to M2 is considered a promising approach, yet no drug specifically modulating this transition has been identified. The spleen tyrosine kinase (Syk) has emerged as a potential therapeutic target due to its role in regulating AD risk genes and promoting Amyloid-β (Aβ) clearance. Herein, a microglial reporter gene screening model targeting Syk is developed and two small molecules, neochlorogenic acid (NCGA) and L-arabinitol (L-Ara), that can upregulate Syk gene expression, leading to the activation of MG M2 phenotype, are identified. Furthermore, these compounds markedly enhance the capacity of MG to migrate toward Aβ and phagocytose Aβ. However, when Syk expression is silenced using shRNA, the ability of these small molecules to induce the MG M2 phenotype and promote Aβ phagocytosis by MG is substantially attenuated. These findings offer new insights into AD therapy development.