Open AccessTransforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein
Author(s) -
Yuichi Hashimoto,
Tomohiro Chiba,
Marina Yamada,
Mikiro Nawa,
Kohsuke Kanekura,
Hiroaki Suzuki,
Kenzo Terashita,
Sadakazu Aiso,
Ikuo Nishimoto,
Masao Matsuoka
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.21.9304-9317.2005
Subject(s) - biology , transforming growth factor , heterotrimeric g protein , programmed cell death , amyloid precursor protein , microbiology and biotechnology , transforming growth factor beta , receptor , caspase , mutation , apoptosis , signal transduction , alzheimer's disease , gene , biochemistry , medicine , g protein , disease
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 Go , 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 theAPP 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.