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Molecular and Cellular Biology, November 2005, p. 9304-9317, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9304-9317.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß2 Is a Neuronal Death-Inducing Ligand for Amyloid-ß Precursor Protein

Yuichi Hashimoto,1 Tomohiro Chiba,1 Marina Yamada,1,2 Mikiro Nawa,1,2 Kohsuke Kanekura,1 Hiroaki Suzuki,1,2 Kenzo Terashita,1 Sadakazu Aiso,2 Ikuo Nishimoto,1 and Masaaki Matsuoka1*

Department of Pharmacology,1 Department of Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan2

Received 27 May 2005/ Returned for modification 8 July 2005/ Accepted 9 August 2005

APP, amyloid ß precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor ß2 (TGFß2), but not TGFß1, binds to APP. The binding affinity of TGFß2 to APP is lower than the binding affinity of TGFß2 to the TGFß receptor. On binding to APP, TGFß2 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 TGFß2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGFß2 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 TGFß2 was upregulated in AD brains, it is speculated that TGFß2 may contribute to the development of AD-related neuronal cell death.

* Corresponding author. Mailing address: Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81-3-5363-3751. Fax: 81-3-3359-8889. E-mail: sakimatu{at}sc.itc.keio.ac.jp.

Molecular and Cellular Biology, November 2005, p. 9304-9317, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9304-9317.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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