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. Towards this objective we have initiated studies of gamma irradiation-induced cell death in quiescent normal T lymphocytes. We find that the DNA damage signal does not effectively induce NF-kB in these cells, and that cell death is p53-dependent. We have standardized conditions to transfect primary cells with small interfering RNAs and developed lentiviral gene transduction to express mutated genes in quiescent cells. With these methodolgies in hand we plan to excamine the triple transgenic mice during the coming year.
