Increased neuronal and glial expression of protein kinase C isoforms in neocortex of transgenic Tg2576 mice with amyloid pathology

We investigated the influence of five- to sevenfold neuronal overexpression of the Swedish mutation of human APP695 (APPsw) in the transgenic mouse st rain Tg2576 on neocortical protein kinase C (PKC) expression and subcellula r distribution. Using specific antibodies to PKC alpha, PKC beta, PKC gamma , PKC epsilon and PKC zeta isoforms for Western blot analysis, we observed increased immunoreactivity for PKC alpha and PKC gamma isoforms in crude ti ssue homogenates from the neocortex of 16-month-old APPsw mice as compared with nontransgenic littermates, which was not present in 6 month-old Tg2576 mice. We also observed elevated levels of PKC alpha, PKC beta, PKC gamma a nd PKC zeta in membrane fractions and reduced concentrations of PKC alpha a nd PKC gamma in cytosolic fractions of aged Tg2576 mice, indicating that th ese PKC isoforms are in their activated state. In young, 6-month-old Tg2576 mice, however, the increase in membrane-bound PKC isoforms and concomitant decrease in cytosolic PKC isoforms was much less pronounced, demonstrating the age-dependent nature of alterations in PKC isoforms. Immunocytochemist ry of brain sections supported these findings and revealed increased neuron al labelling for PKC alpha, PKC gamma and PKC lambda isoforms in neocortex of 16-month-old APPsw mice compared with nontransgenic littermates, with th e increase being strongest for PKC gamma and PKC lambda isoforms. Additiona lly, PKC gamma and to a lesser extent PKC lambda isoforms were induced in r eactive astrocytes in proximity to amyloid plaques. Our data indicate that neuronal overexpression of APPsw causes a dynamic change in neuronal expres sion and activation of multiple PKC isoforms known to be regulators of prot eolytic amyloid precursor protein (APP) processing (PKC alpha) and of neuro nal survival (PKC lambda and PKC zeta). The induction of the PKC gamma and PKC lambda isoforms in reactive astrocytes surrounding amyloid plaques migh t be required for astrocyte activation and astrocytic cytokine expression i n response to amyloid plaque formation.