Transforming growth factor β2 is a neuronal death-inducing ligand for amyloid-β precursor protein

APP, amyloid beta precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor beta 2 (TGF beta 2), but not TGF beta 1, binds to APP. The binding affinity of TGF beta 2 to APP is lower than the binding affinity of TGF beta 2 to the TGF beta receptor. On binding to APP, TGF beta 2 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 TGF beta 2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGF beta 2 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 TGF beta 2 was upregulated in AD brains, it is speculated that TGF beta 2 may contribute to the development of AD-related neuronal cell death.