Amelioration of amyloid -FcRIIb neurotoxicity and tau pathologies by targeting LYN

Abstract

SRC-family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid (A)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fc receptor IIb2 (FcRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to A 1-42 (A(1-42)). Knockdown of LYN expression inhibited A(1-42)-induced neuronal cell death. Of note, LYN interacted with FcRIIb2 upon exposure to A(1-42) and phosphorylated FcRIIb2 at Tyr273 within immunoreceptor tyrosine-based inhibitory motif in neuronal cells. With the use of the structure-based drug design, we isolated KICG2576, an ATP-competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half-maximal inhibitory concentration value of 0.15 M. KICG2576 inhibited A- or FcRIIb2-induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to A, KICG2576 blocked the phosphorylation of FcRIIb2 and translocation of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, a binding protein to the phosphorylated FcRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of A(1-42)-FcRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated A-induced memory impairment. These results suggest that LYN plays a crucial role in A(1-42)-mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.Gwon, Y., Kim, S.-H., Kim, H. T., Kam, T.-I., Park, J., Lim, B., Cha, H., Chang, H.-J., Hong, Y. R., Jung, Y.-K. Amelioration of amyloid -FcRIIb neurotoxicity and tau pathologies by targeting LYN.