Our earlier studies indicated that TGF beta 2-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 TGF beta 2-mediated neuronal cell death via APP by attenuating the binding of TGF beta 2 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 TGF beta 2 to APP. This mechanism may contribute to the onset and the progression of Alzheimer's disease-relevant neuronal cell death. (C) 2010 Elsevier Inc. All rights reserved.