An immunohistochemical study was performed to evaluate the stress-related proteins heat shock protein 25 (HSP25) and metallothionein 1+2 (MT1+2) in the brains of a murine model of bovine spongiform encephalopathy (BSE). Transgenic mice (BoTg110) expressing the bovine cellular prion protein were intracerebrally inoculated with brainstem homogenate from BSE infected cattle. PrP(BSE) deposits were found in the brain as early as 150 days post-inoculation (dpi) and in mice sacrificed terminally at 290-320dpi. Glial proliferation and spongiform change were associated with an increase in glial immunostaining of MT1+2 and HSP25, respectively. These proteins are associated with oxidative stress and heavy metal metabolism, which may have a role in the pathogenesis of BSE.