Reactive oxygen intermediates during programmed cell death induced in the thymus of the Ts(17(16))65Dn mouse, a murine model for human Down's syndrome

Down's syndrome (DS) is one of the most frequent genetic disorders in human s. It has been suggested that overexpression of copper-zinc superoxide dism utase (SOD-1) in DS may be involved in some of the abnormalities observed, mainly neurodegenerative and immunopathological processes. One of the conse quences is early thymic involution, Recently, Ts(17(16))65Dn mice (Ts65Dn m ice), made segmentally trisomic for a chromosome 16 segment, fulfill the cr iteria for a DS model. To study the possible role of SOD-1 overexpression i n thymocyte biology, we analyzed the role of reactive oxygen intermediates during in vivo and in vitro programmed cell death (PCD) induced in the thym us of Ts65Dn mire, Our main findings can be summarized as follows. Ts65Dn t hymuses exhibit greater PCD activity than controls, as ascertained by a com bination of morphological, histochemical, and ultrastructural procedures. T s65Dn thymocytes were highly susceptible to PCD induced by both LPS (in viv o) and dexamethasone, a synthetic glucocorticoid agonist (both in vivo and in vitro). Thymus abnormalities were probably caused by SOD-1 hyperexpressi on in Ts65Dn cells, in that reactive oxygen intermediate generation (specif ically H2O2 production) is enhanced in thymocytes and clearly correlates wi th apoptosis, Similarly, oxidative injury correlated with the formation of Lipid peroxidation by-products and antioxidants which partly inhibit PCD in thymocytes.