Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

• DOI: 10.1096/fj.201800926r
• Publication Date: 2018-12-12T19:27:13Z
• Authors: Youngdae Gwon; Seo-Hyun Kim; Hyun Tae Kim; Tae-In Kam; Jisu Park; Bitna Lim; Hyunju Cha; Ho-Jin Chang; Yong Rae Hong; Yong-Keun Jung
• Keywords: LYN; Hyperphosphorylation; Neurotoxicity; FYN; Src family kinase

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 amyloid β (Aβ)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found enzyme activity increased the brain AD patients promoted neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown expression inhibited Aβ1–42-induced cell death. Of note, interacted with FcγRIIb2 upon exposure Aβ1–42 phosphorylated at Tyr273 within immunoreceptor tyrosine-based inhibitory motif cells. With use structure-based drug design, isolated KICG2576, ATP-competitive inhibitor LYN. Determination cocrystal structure illustrated KICG2576 bound cleft kinase domain a half-maximal concentration value 0.15 µM. Aβ- or FcγRIIb2-induced death, this effect better than pyrazolopyrimidine 1, widely used SFK. Upon Aβ, blocked phosphorylation translocation phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, binding protein FcγRIIb2, plasma membrane, resulting inhibition hyperphosphorylation, downstream event Aβ1–42-FcγRIIb2 binding. Furthermore, intracerebroventricular injection into mice ameliorated Aβ-induced memory impairment. These results suggest crucial Aβ1–42-mediated pathology, providing therapeutic potential AD.—Gwon, Y., Kim, S.-H., H. T., Kam, T.-I., Park, J., Lim, B., Cha, H., Chang, H.-J., Hong, Y. R., Jung, Y.-K. Amelioration β-FcγRIIb pathologies targeting FASEB J. 33, 4300–4313 (2019). www.fasebj.org