Gamma-secretase is an aspartyl protease composed of four proteins: presenilin (PS), nicastrin (Nct), APH1, and PEN2. These proteins assemble into a membrane complex that cleaves a variety of substrates within the transmembrane domain. The gamma-secretase cleavage products play an important role in various biological processes such as embryonic development and Alzheimer's disease (AD). The major role of gamma-secretase in brain pathology has been linked to AD and to the production of the amyloid beta-peptide. However, little is known about the possible role of gamma-secretase following acute brain insult. Here we examined by immunostaining the expression patterns of two gamma-secretase components, PS1 and Nct, in three paradigms of brain insult in mice: closed head injury, intracerebroventricular injection of LPS, and brain stabbing. Our results show that in naïve and sham-injured brains expression of PS1 and Nct is restricted mainly to neurons. However, following insult, the expression of both proteins is also observed in nonneuronal cells, consisting of activated astrocytes and microglia. Furthermore, the proteins are coexpressed within the same astrocytes and microglia, implying that these cells exhibit an enhanced gamma-secretase activity following brain damage. In view of the important role played by astrocytes and microglia in brain disorders, our findings suggest that gamma-secretase may participate in brain damage and repair processes by regulating astrocyte and microglia activation and/or function.