GLIAL NEURONAL INTERACTIONS IN CELL CULTURE MODELS

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The shared pathological processes that initiate Alzheimer's disease likely reflect aberrancies in basic aspects of cell biology and thus are amenable to study through cell culture approaches, which offer a degree (and rate) of manipulation unavailable in other models. In this project, tissue culture models will be used to test various aspects of glial and neuronal interactions theoretically operative in Alzheimer's. Preliminary astroglial and microglial culture, neuronal cultures, and relevant cell lines will be utilized to assay the effects of cytokines on parameters being explored in other projects because of their potential importance in the initiation and/or progression of Alzheimer's and related conditions. This project is focused on the hypothesis that S100beta and other glial cytokines modulate neuritic and synaptic integrity, and that this modulation can involve pathogenic over- expression of betaAPP. These interactions appear to be at the root of Alzheimer pathology and clinical dementia; they will be explored through three specific aims. Aim 1: Determine the effects of S100beta on expression and processing of betaAPP. Initial studies have shown that S100beta can elevate betaAPP, which has implications for both amyloid deposition and aberrant neuritogenesis. Proposed studies will determine mechanisms involved in this induction and its relevance to neurite growth and amyloid production. Aim 2: Determine the potential influence of cytokines on the interaction between calcium homeostasis, neuritic outgrowth, and synapses. While S100beta elevates betaAPP, it also could have unrelated effects on neuronal processes and connections through its impact on calcium levels. A more general influence on these parameters is indicated for other cytokines, as well. Determine the effectiveness of anti-inflammatory cytokines and rugs against glial and neuronal activation. The primary endpoint in aim 3 will be microglial activation, with the goal of reducing production of cytokines and neurotoxins which negatively impact neuronal health and function. However, it is also plausible that direct effects of pro-inflammatory cytokines on neurons may be susceptible to manipulation by drugs that target basic cytokine signaling events. Accomplishment of these goals will be of direct benefit to the identification of basic elements of Alzheimer's pathology and potential sites for therapeutic intervention.