TY - JOUR
T1 - Amelioration of amyloid β-FcγRIIb neurotoxicity and tau pathologies by targeting LYN
AU - Gwon, Youngdae
AU - Kim, Seo Hyun
AU - Kim, Hyun Tae
AU - Kam, Tae In
AU - Park, Jisu
AU - Lim, Bitna
AU - Cha, Hyunju
AU - Chang, Ho Jin
AU - Hong, Yong Rae
AU - Jung, Yong Keun
N1 - Funding Information:
The authors thank Dr. D. Selkoe (Harvard Medical School, Boston, MA, USA) for CHO and 7PA2 cells, Harvard Brain Tissue Center of McLean Hospital for human brain tissues, and Jeong Eun Na (Crystalgenomics Inc.) for technical assistance. This work was also supported by a Creative Research Initiative (CRI) Grant (NRF-2016R1A2A1A05005304), and by the Bio and Medical Technology Development Program of the National Research Foundation Grant (NEF-2017M3A9G7073521), funded by the Ministry of Education, Science, and Technology (South Korea). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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 β (Aβ)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown of LYN expression inhibited Aβ1–42-induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aβ1–42 and phosphorylated FcγRIIb2 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 µM. KICG2576 inhibited Aβ- or FcγRIIb2-induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aβ, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aβ1–42-FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aβ-induced memory impairment. These results suggest that LYN plays a crucial role in Aβ1–42-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 β-FcγRIIb neurotoxicity and tau pathologies by targeting LYN. FASEB J. 33, 4300–4313 (2019). www.fasebj.org.
AB - 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 β (Aβ)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown of LYN expression inhibited Aβ1–42-induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aβ1–42 and phosphorylated FcγRIIb2 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 µM. KICG2576 inhibited Aβ- or FcγRIIb2-induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aβ, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aβ1–42-FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aβ-induced memory impairment. These results suggest that LYN plays a crucial role in Aβ1–42-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 β-FcγRIIb neurotoxicity and tau pathologies by targeting LYN. FASEB J. 33, 4300–4313 (2019). www.fasebj.org.
KW - Alzheimer's disease
KW - Aβ
KW - cocrystallization
KW - memory impairment
UR - http://www.scopus.com/inward/record.url?scp=85079883523&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079883523&partnerID=8YFLogxK
U2 - 10.1096/fj.201800926R
DO - 10.1096/fj.201800926R
M3 - Article
C2 - 30540497
AN - SCOPUS:85079883523
SN - 0892-6638
VL - 33
SP - 4300
EP - 4313
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -