The Role Of TREM2 Mediated Microglial Migration In The Pathogenesis Of AD

Triggering receptor expressed on myeloid cells 2(TREM2)is expressed by microglia in the brain.The coding variants of TREM2 have been reported to increase the risk for Alzheimer's disease(AD),Nasu-Hakola disease(NHD)and other neurodegenerative diseases.Despite recent progress,how mutation in TREM2 contributes to disease progress remains to be elucidated.Firstly,we created a stab wound injury in wildtype(WT)and Trem2-/-(TREM2 knockout,KO)mice.Using immunohistochemical and immunofluorescent staining,we confirmed the decreased microglial migration to injury site in Trem2-/-mice.It was also verified in vitro that similar to Trem2-/-primary microglia,Trem2 knockdown microglia showed reduced migration than WT.Next,we found that TREM2 deficiency led to decreased phosphorylation of focal adhesion kinase(FAK)and inactivation of Racl/Cdc42,both of which play crucial role in cell migration.Previous study has verified the interaction of A(3 with TREM2.To test whether A?-regulated microglial migration is dependent on TREM2,WT and Trem2-/-primary microglia were treated with oA?42,and the FAK/Racl/Cdc42 signaling pathway could only be seen activated in WT cells.Consistent with this phenomenon,reorganization of actin filaments and fulopodia formation were obvious in WT but not Trew2-/-microglia.In addition,microglia in TREM2 R47H mice showed decreased migration to injected AP,supporting the opinion that it is a loss-of-function variant.Finally,the motility of TREM2-depleted microglia could be restored with Racl/Cdc42 specific activator CN04 in vitro and in vivo.Microglia are innate immune cells in the brain,alterations in microglia functionality are implicated in brain development and aging,as well as in neurodegeneration,and the rare mutation of TREM2 is found to increase the risk of AD.Here we demonstrate that TREM2 promotes microglial migration and reveal that AD-associated variant exhibits loss-of-function in response to Ap.Our study suggests a novel signaling pathway that modulate microglial migration and might be a potential target to ameliorate the outcome of AD.