TAG-1 is an inhibitor of TGFbeta2-induced neuronal death via amyloid beta precursor protein.
Our earlier studies indicated that TGFbeta2-induced neuronal cell death by binding to the extracellular domain of amyloid beta precursor protein (APP) on the cell surface and by triggering an intracellular death signal pathway, mediated by a heterotrimeric G protein Go, Rac1/cdc42, ASK1, JNK, NADPH oxidase, and caspases in this order. Recently, transient axonal glycoprotein-1 (TAG-1), a glycophosphatidylinositol-linked protein, was identified as another natural ligand of APP. TAG-1 increases APP intracellular domain release and triggers FE65-dependent transcriptional activity in a gamma-secretase-dependent manner by binding to APP. In this study, we show that TAG-1 inhibits TGFbeta2-mediated neuronal cell death via APP by attenuating the binding of TGFbeta2 to APP in a gamma-secretase-independent manner. TAG-1 is expressed in murine hippocampal neurons at 8 weeks of age, but its expression is reduced at 8 and 20 months. These findings suggest that an age-related reduction of TAG-1 expression may predispose neurons to cell death, induced by the binding of TGFbeta2 to APP. This mechanism may contribute to the onset and the progression of Alzheimer's disease-relevant neuronal cell death.
Tachi
Nobuyuki
N
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Tokyo 160-8402, Japan.
Hashimoto
Yuichi
Y
Nawa
Mikiro
M
Matsuoka
Masaaki
M
D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D058969:Contactin 2; D015536:Down-Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; D058969:Contactin 2; D016212:Transforming Growth Factor beta