Alzheimer disease is characterized by neuronal loss which leads to dementia. Three genes considered to be particularly important in the development of brain plaques are amyloid precursor protein (APP), presenelin and tau. A recent triple transgenic model, incorporating all three genes, shows striking similarity to many aspects of AD. However, the mechanism of neuronal cell death remains unclear.? ? T lymphocytes undergo various forms of cell death. The two forms that may be mechanistically related to neuronal death are those induced by DNA damage or the loss of homeostatic survival signals, because these occur in the absence of cell prolieration. The transcription factor NF-kB has been implicated in providing anti- and pro-apoptotic signals depending on the cell type and the mode of cell death. We propose to use T cells from the triple transgenic mice to investigate whether, and how, expression of the mutant genes affects T cell viability. The underlying hypothesis is that understanding quiescent T cell death in the triple transgenics will provide insight into the mechanism of quiescent neuronal cell death realted to AD. ? ? We compared gamma-irradiation induced cell death in B and T lymphocytes. Both cell types underwent p53-dependent apoptosis, but B cells were significantly more sensitive as determined by the dose/response, or kinetics of cell death at a fixed dose. We further investigated the basis fro the difference in several genetically alterd mouse strains. The conclusions from these studies is that the difference between the two cell types is due to a difference in the basal redox state of resting lymphocytes. In accordance with this idea, we can alter the apoptotic response by altering the levels of reactive oxygen species (ROS). This unexpected result may be particularly relevant to proposed connections between ROS, aging and age-related dementias.
