Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

Abstract

APP, amyloid β precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor β2 (TGFβ2), but not TGFβ1, binds to APP. The binding affinity of TGFβ2 to APP is lower than the binding affinity of TGFβ2 to the TGFβ receptor. On binding to APP, TGFβ2 activates an APP-mediated death pathway via heterotrimeric G protein G_o, c-Jun N-terminal kinase, NADPH oxidase, and caspase 3 and/or related caspases. Overall degrees of TGFβ2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGFβ2 induce neuronal death in primary cortical neurons, whose one allele of the APP gene is knocked in with the V642I mutation. Combined with the finding indicated by several earlier reports that both neural and glial expression of TGFβ2 was upregulated in AD brains, it is speculated that TGFβ2 may contribute to the development of AD-related neuronal cell death.

ACKNOWLEDGMENTS

We are indebted to Masaki Kitajima for essential support to this study; Mark C. Fishman for F11 neuronal hybrid cells; John T. Potts, Jr., Etsuro Ogata, Yoshiomi Tamai, and Yumi Tamai for indispensable support; and Dovie Wylie for expert technical assistance. We especially thank Takako Hiraki and Tomo Yoshida-Nishimoto for essential assistance.

This work was supported in part by grants from the Takeda Science Foundation (Y.H. and M.M.), a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (T.C., M.Y., and H.S.), and The Japan Society for the Promotion of Science.