Aβ plaque-associated glial reaction as a determinant of apoptotic neuronal death and cortical gliogenesis: a study in APP mutant mice

The purpose of this study was to investigate the microglia-driven apoptosis and the A beta deposits triggered generation of new microglial cells in the neocortex of TgCRND8 mice. Three- and seven-month-old TgCRND8 mice, displaying an early and widespread amyloid deposition, respectively, were used. In 7-month-old TgCRND8 mice the A beta-associated glial reaction was accompanied by an intense immunoreactivity of both TNF-alpha and inducible nitric oxide synthase, increased immunoreactivity of the pro-apoptotic protein Bax and a decrease in levels of the anti-apoptotic protein Bcl-2.Cortical and hippocampal neurons of TgCRND8 mice displayed higher immunoreactivity and higher nuclear expression of the transcription factor NF-kB than controls. It is possible that such an increase could represent a defence/compensatory response to degeneration. These findings indicate that A beta deposits activate brain-resident microglia population and astrocytes, and induce overproduction of inflammatory mediators that enhance pro- and anti-apoptotic cascades. In both 3- and 7-month-old TgCRND8 mice apparent gliogenesis was present in the vicinity of A beta plaques in the neocortex, indicating that microglia have a high proliferative rate which might play a more complex role than previously acknowledge.