Differential expression of ADAM15 and ADAM17 metalloproteases in the rat brain after severe hypobaric hypoxia and hypoxic preconditioning

The ADAMs (a disintegrin and metalloprotease) are a family of membrane-anchored glycoproteins capable of shedding a multitude of proteins from the cell surface. Although ADAMs are being considered as crucial modulators of physiological and pathophysiological processes, their roles in neuronal death/survival are largely unexplored. In the present study, changes in brain expression of ADAM15 and ADAM17 (TACE) have been quantitatively examined in rats in response to injurious severe hypoxia (SH) and in animals which acquired hypoxic tolerance through preconditioning to mild hypoxia prior SH. SH persistently up-regulated ADAM15 mRNA and protein levels in hippocampus and neocortex but not in thalamus or hypothalamus. This effect was not observed in the preconditioned rats tolerant to SH. In contrast, hippocampal levels of ADAM17 mRNA and neocortical levels of ADAM17 mRNA and protein were largely reduced following SH in non-preconditioned rats. Hypoxic preconditioning prevented down-regulation of the adam17 gene and considerably enhanced ADAM17 protein expression in hippocampus and neocortex in response to SH. The present findings implicate ADAM15 in the processes of neuronal hypoxic injury. On the other hand, these results also provide evidence for a pro-survival neuroprotective role of ADAM17 and its engagement in the process of preconditioning-induced hypoxic tolerance. The analysis of the protein levels of soluble and membrane-bound forms of APP in the neocortex and hippocampus of rats subjected to SH and SH with preconditioning has demonstrated that an increased ADAM17 expression in preconditioned animals 24 h after hypoxia corresponded to a higher level of soluble form of APP and a reduction of the membrane bound fraction which reflects the role of ADAM17 in APP shedding.

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► ADAM family metalloproteases are essential for brain structure and function.
► Injurious and protective hypoxia modifies neuronal expression of ADAM15 and ADAM17.
► Preconditioning-induced neuronal tolerance is associated with ADAM17 over-expression.
► Preconditioning activates neuroprotective mechanisms averting neurodegeneration.